Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Surveillance and Epidemiology Review (OSE)
Office of Pharmacovigilance and Epidemiology (OPE)
Integrated Drug Utilization, Epidemiology and Pharmacovigilance Review:
Benzodiazepine Use, Misuse, Abuse, Dependence, Withdrawal, Morbidity, andMortality
Date:

9/24/2020

Reviewers:

Amy Seitz, PhD, MPH, Epidemiology Reviewer
Saranrat Wittayanukorn, PhD, Epidemiology Reviewer
Shekhar H. Mehta, PharmD, MS, Drug Utilization Analyst
Division of Epidemiology II
Kelly Harbourt, PharmD, BCCCP, Safety Evaluator
Division of Pharmacovigilance I

Quality Control:

Sara Karami, PhD, MPH, Epidemiology Reviewer
Christina Greene, PhD, Epidemiology Reviewer
Division of Epidemiology II

Team Leaders:

Rose Radin, PhD, MPH
Division of Epidemiology II
Corinne Woods, RPh, MPH
Division of Epidemiology II
Vicky Chan, PharmD, BCPS
Division of Pharmacovigilance I

Tertiary Reviewers:

Jana McAninch, MD, MPH, MS
Senior Medical Epidemiologist
Division of Epidemiology II
Travis Ready, PharmD, MS
Division of Epidemiology II
Cindy Kortepeter, PharmD
Director, Division of Pharmacovigilance I

Office-level Clearance:

Reference ID: 4675389

Judy Staffa, PhD, RPh
Associate Director for Public Health Initiatives

Grace Chai, PharmD
Associate Director for Special Initiatives (Acting)
Office of Surveillance and Epidemiology
Drug Names:

alprazolam, chlordiazepoxide, clobazam, clonazepam,
clorazepate, diazepam, estazolam, flurazepam, lorazepam,
midazolam, oxazepam, quazepam, temazepam, triazolam

Subject:

Review of benzodiazepine use, misuse, abuse, dependence,
withdrawal, morbidity, and mortality

OSE RCM #:2019-800**This document contains proprietary drug use data obtained by FDA undercontract. The drug use data/information cannot be released to the public/non-FDA
personnel without contractor approval obtained through the FDA/CDER Office ofSurveillance and Epidemiology.**2

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TABLE OF CONTENTSGLOSSARY .................................................................................................................................... 5
EXECUTIVE SUMMARY ............................................................................................................. 6
1 INTRODUCTION ................................................................................................................. 14
Background ................................................................................................................... 15
Regulatory History and Pharmacology.......................................................................... 16
Product Labeling ........................................................................................................... 18
2 REVIEW METHODS AND MATERIALS .......................................................................... 26
Overview and Framework ............................................................................................. 26
Drug Utilization Analyses ............................................................................................. 29
The National Survey on Drug Use and Health .............................................................. 29
Monitoring The Future .................................................................................................. 30
American Association of Poison Control Centers, National Poison Data System ........ 31
National Electronic Injury Surveillance System–Cooperative Adverse Drug Event
Surveillance ............................................................................................................................... 33
Treatment Episode Data Set - Admissions .................................................................... 34
National Vital Statistics System-Mortality .................................................................... 34
Literature Review .......................................................................................................... 35
FDA Adverse Event Reporting System ......................................................................... 36
3 REVIEW RESULTS ............................................................................................................. 40
Drug Utilization Analyses ............................................................................................. 40
The National Survey on Drug Use and Health .............................................................. 50
Monitoring the Future.................................................................................................... 51
American Association of Poison Control Centers, National Poison Data System ........ 52
National Electronic Injury Surveillance System–Cooperative Adverse Drug Event
Surveillance ............................................................................................................................... 59
Treatment Episode Data Set-Admissions ...................................................................... 61
National Vital Statistics System-Mortality .................................................................... 63
Literature Review .......................................................................................................... 68
FAERS........................................................................................................................... 71
4 DISCUSSION ....................................................................................................................... 95
Use, Misuse, and Abuse of Benzodiazepines and Associated Morbidity and Mortality 95
Dependence and Withdrawal ......................................................................................... 98
Considerations for Regulatory Actions ......................................................................... 99
Data and Methods Considerations ............................................................................... 100
5 CONCLUSIONS ................................................................................................................. 104
6 RECOMMENDATIONS .................................................................................................... 104
7 REFERENCES .................................................................................................................... 106
8 APPENDICES ..................................................................................................................... 110
Appendix A. Drug Utilization ..................................................................................... 110
Appendix B. American Association of Poison Control Centers.................................. 124
Appendix C. National Electronic Injury Surveillance System–Cooperative Adverse
Drug Event Surveillance.......................................................................................................... 136
Appendix D. National Vital Statistics System-Mortality ............................................ 138

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Appendix E. Literature Review ................................................................................... 142
Appendix F. Literature Review Abstraction................................................................ 159
Appendix G. Pharmacovigilance Data and Descriptions ............................................ 170

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GLOSSARY
AAPCC

American Association of Poison Control CentersAEadverse event

CDC

Centers for Disease Control and Prevention

CNS

central nervous system

CSA

Controlled Substance Act

CSS

Controlled Substance Staff

DEA

Drug Enforcement Administration

DEPI

Division of Epidemiology

DP

Division of Psychiatry

DPV

Division of Pharmacovigilance

DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth EditionEDemergency department

FAERS

FDA Adverse Event Reporting System

ICD-10International Classification of Diseases, Tenth Revision

IDV

Symphony Health Integrated Dataverse®

MedDRA

Medical Dictionary for Regulatory Activities

NCHS

National Center for Health Statistics

NEISS-CADESNational Electronic Injury Surveillance System – Cooperative Adverse
Drug Event Surveillance

NPDS

National Poison Data System

NPA

IQVIA National Prescription Audit™

NSDUH

National Survey on Drug Use and Health

NSP

IQVIA National Sales Perspectives™

NVSS-M

National Vital Statistics System - Mortality

OSE

Office of Surveillance and Epidemiology

PCC

poison control center

PLR

Physician Labeling RulePT

Preferred Term

PTSD

posttraumatic stress disorder

SAMHSA

Substance Abuse and Mental Health Services Administration

SMQ

Standardised MedDRA Query

SUD

substance use disorder

TEDS

Treatment Episode Data Set - Admissions

TPT

IQVIA Total Patient Tracker™

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EXECUTIVE SUMMARY
Background
The purpose of this review is to inform potential class labeling changes for(b) (5)benzodiazepines
The
Division of Epidemiology II (DEPI) and the Division of Pharmacovigilance (DPV)
undertook a review of available data to describe benzodiazepine use, abuse, misuse,dependence, withdrawal, and associated adverse events (AEs), including death.
Specifically, the objectives of this review are to: describe the current scope, trends, andpatterns of benzodiazepine prescribing, misuse, abuse, and morbidity and mortality in the
U.S.; stratify outcomes by the involvement of benzodiazepines alone vs. concomitantlywith opioids and other substances (e.g., alcohol, marijuana, stimulants); review publishedepidemiologic studies on the risks of abuse, misuse, addiction, dependence, and overdose
associated with long-term use of benzodiazepines, as well as to identify potential
predictors of long-term use and dependence; identify vulnerable populations and risk
factors for misuse, abuse, dependence, addiction, and overdose; provide a high-level
overview of all reports of benzodiazepine abuse, dependence, or withdrawal received in
the FDA Adverse Event Reporting System (FAERS), including distribution by age, sex,
outcome, geographic location, and frequency of AEs reported; and conduct a report-level
analysis of direct reports of benzodiazepine abuse, dependence, or withdrawal retrieved
from FAERS in order to describe characteristics of these cases in more detail, including
specific symptoms and time to onset of dependence, as well as reported duration andspecific symptoms of withdrawal.
Data Sources and Methods
DEPI accessed proprietary drug utilization databases available to the FDA and examineddata from national surveys, substance use disorder (SUD) treatment admissions, calls to
U.S. poison control centers, emergency department (ED) visits, and death certificates.
DEPI also searched the published literature for articles on risks of misuse, abuse, andaddiction associated with benzodiazepine use, factors associated with long-term
benzodiazepine use and dependence, and social factors influencing preferences for abuseof specific benzodiazepine drugs. DPV conducted a search of FAERS and describedcharacteristics of and outcomes involved in benzodiazepine reports of drug abuse,dependence, and withdrawal.
I.

Drug Utilization
Nationally estimated sales distribution and dispensed prescription data fromthe following proprietary databases available to the FDA were used to conduct
analyses of drug utilization for benzodiazepines
o
o
o
o

II.

IQVIA, National Sales Perspectives™ database, 2018
IQVIA, National Prescription Audit™ database, 2014-2018
IQVIA, Total Patient Tracker™ database, 2014-2018
Symphony Health, Integrated Dataverse®, 2015-2018

Epidemiologic data

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•Annually from 2015 to 2018, approximately 5.4 million (2.0%) U.S. individuals aged
12 and older are estimated to have misused or abused benzodiazepines. The highest
prevalence was in the 18-25 year-old age group, in which almost half of past-year
benzodiazepine users reported misusing or abusing the drugs. The most commonly
reported reasons for benzodiazepine misuse or abuse were to “relax or relievetension” (46.3%), “help with sleep” (22.4%), “get high or [respondent] was hooked”(11.8%), “help with emotions” (10.5%), and “experiment or to see what the drug islike” (5.7%).

•

Among 12th graders, estimated nonmedical use of several commonly usedbenzodiazepines has declined over the past decade, paralleling downward trends inuse of multiple other prescription and illicit drugs in this group.

•

In 2016, the nationally estimated number of ED visits due to nonmedical use of
benzodiazepines (n=167,845), was higher than the corresponding estimate forprescription opioids (n=129,863), although a relatively small proportion of visits
involved benzodiazepines alone—13.9% (n=23,335) compared to 31.2% (n=40,499)
for visits due to prescription opioid nonmedical use.

•

There was a high frequency of exposure calls to U.S. poison centers involving
benzodiazepine misuse or abuse, and trends were generally consistent withprescribing trends. The annual number of exposure calls involving a benzodiazepine
misuse or abuse increased from 10,156 in 2009 to 10,738 in 2011, then decreased to
8,761 in 2017. However, the observed declines in benzodiazepine exposure calls
were driven by calls with minor clinical effects, whereas benzodiazepines exposure
calls with more severe medical outcomes increased across the study period.
Approximately 63% of benzodiazepine misuse/abuse calls in 2017 involved multiple
substances—most commonly prescription opioids, alcohol, or stimulants—andmedical outcomes in these cases are more severe than in cases involving
benzodiazepines alone. The distribution of medical outcome severity in singlesubstance misuse/abuse calls was similar across the five most commonly prescribedbenzodiazepines.

•

Upon analysis of 15,779 single-substance benzodiazepine exposure calls reported to
U.S. poison centers specifically involving abuse between 2009-2017, 15% (n=2,394)
reported moderate-to-severe medical outcomes in patients with clinical effects related
to the exposure. The most commonly reported related clinical effects andcorresponding frequency in these exposures included drowsiness/lethargy (76%),slurred speech (24%), confusion (14.1%), tachycardia (13.3%), hypotension (13.3%),
and ataxia (13.1%).

•

Benzodiazepine-involved poisoning deaths increased from 1,298 in 2010 to 11,537 in
2017. The proportion of deaths due to benzodiazepines alone was small anddecreased over this period, from 8.6% in 2000 to 2.7% in 2017. From 2013-2017,55.4% of benzodiazepine-involved fatal poisonings also involved prescription
opioids, but only 9.7% involved benzodiazepines and prescriptions opioids without
mention of any additional substances.

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•

We identified no high-quality longitudinal studies assessing the risk of addiction
associated with benzodiazepine use. However, in 2017, 1.2% of admissions(n=10,316) to publicly-funded substance use disorder treatment programs indicatedthat benzodiazepines were the primary drug of abuse, compared to 3.1% for opioid
analgesics. An additional 7.3% and 9.8% of admissions indicated benzodiazepines as
the secondary and tertiary drug of abuse, respectively. In one published analysis of
NSDUH data from 2015-2016, an estimated 0.5 million people ages 18 and older
annually reported misuse or abuse of benzodiazepines, did not report misuse or abuseof other sedatives, hypnotics, or anxiolytics, and met the criteria for Sedative,
Hypnotic, or Anxiolytic Use Disorder, per the Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition (DSM-IV). Although these data cannot be used toestimate the risk of benzodiazepine addiction associated with use of these
medications, they indicate that both primary benzodiazepine use disorders andpolysubstance addiction involving benzodiazepines do occur.

FAERS Data: High-level Overview
The high-level overview of FAERS reports revealed that, after exclusion of those reports
also included in NPDS to avoid duplicate counts with DEPI’s NPDS analysis, almost
44,000 reports related to benzodiazepine abuse, dependence, or withdrawal were reported
to FDA from the time of approval through June 30, 2019, of which approximately 24%
involved a concomitant opioid. The most frequently reported PTs across the top fourmost frequently reported benzodiazepines (in descending order: alprazolam, diazepam,
lorazepam, clonazepam) were similar and mostly related to overdose, abuse, dependence,or withdrawal. There were slight differences in distribution of PTs across the four drugs,
but no major differences were noted. Sixty percent of all fatal reports involving abenzodiazepine also involved a concomitant opioid, with approximately 3% of fatal
reports involving a benzodiazepine as a single drug substance. The remaining fatal
reports involved a benzodiazepine along with one or more of the following, listed indecreasing order of frequency: alcohol, various antidepressants, acetaminophen,zolpidem and various antipsychotics (See Section 3.9.1 and Table 3.17 for additional
details). The FAERS findings were congruent with the epidemiologic data, which
demonstrated high levels of benzodiazepine abuse and increased severity of clinicaleffects when benzodiazepines abuse involved other drugs.
II.

Dependence and Withdrawal

Epidemiologic Data
From 2009 to 2017, the number of calls to U.S. poison centers for benzodiazepine
withdrawal increased from 263 to 372. A small number of published longitudinal studies
described risk factors for long-term or high-dose benzodiazepine use or dependence.
These included female sex, older age, mental health conditions, and concomitant use ofcertain medications (e.g., antidepressants). However, most of these studies wereconducted in non-U.S. populations and had other limitations.
FAERS Data: Report-level Review
The report-level review of 104 FAERS cases of benzodiazepine as single drug substancesubmitted directly to FDA from patients and healthcare providers (i.e., direct reports)

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mostly consisted of reports of dependence or withdrawal occurring with use of abenzodiazepine as prescribed, rather than abuse. Because we limited our search to direct
reports only, there is likely a bias against identifying cases of abuse or illicit use,
especially because most cases in this case series (n=82, 79%) were submitted by thepatients themselves.
We identified dependence and subsequent withdrawal, in some cases with highmorbidity, that developed during therapeutic use of benzodiazepines (clonazepam,
alprazolam, lorazepam, diazepam, triazolam, or oxazepam). Approximately 80% of thecases in this case series described symptoms associated with withdrawal frombenzodiazepines that included mainly central nervous system effects (e.g., insomnia,
increased anxiety or panic attacks, memory impairment, depression), cardiovasculareffects (e.g., heart rate or rhythm fluctuations), and gastrointestinal effects (e.g.,
abdominal pain, nausea, diarrhea). The median time to onset of dependence or tolerance
was within two weeks of initiating use, ranging from one day to four years. The majorityof cases reported a duration of use ranging from months to years, rather than the shortterm use of no more than several weeks currently recommended in some benzodiazepine
product labeling. The median duration of withdrawal symptoms for all benzodiazepines
was approximately 9.5 months and ranged from two weeks to eight years. An important
limitation in the assessment of these cases was the difficulty in differentiating withdrawal
symptoms from potential re-emergence or continuation of symptoms for which the
benzodiazepine was being used. The Drug Abuse and Dependence Section of the current
Xanax product labeling also acknowledges the difficulty of distinguishing withdrawal
and recurrence, especially in patients undergoing dose reduction.
Our analysis of the FAERS dependence and withdrawal cases, coupled with the findingsof prevalent longer-term use and increasing numbers of poison center calls forbenzodiazepine withdrawal, suggest a need for enhanced communication about theserisks and the appropriate management of patients treated with benzodiazepines.
Although benzodiazepine product labeling includes varying recommendations for dosing,duration of use, and tapering schedules, we noted FAERS cases from patients andprescribers who described the need for increased prescriber education about the risk ofdependence and withdrawal even when the drugs are used at therapeutic doses for shortperiods of time, including the lowest available dosages. In addition, the series includes
cases from patients and prescribers who specifically requested additional or more
prominent warnings in benzodiazepine product labeling with respect to the potential for
dependence and subsequent withdrawal, suggesting that additional emphasis on these
serious AEs in the product labeling may be warranted. Based on the cases described in
Section 3.9.2.1, it is possible that if the patients had been managed by the providers
according to recommendations in the product labeling, the serious symptoms ofdependence and subsequent withdrawal may have been lessened or avoided altogether.
Conclusions
In this review, we describe substantial morbidity and mortality associated withbenzodiazepine use, misuse, and abuse, most often in the context of polysubstance use

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(b) (4), (b) (5)2. Consider a Boxed Warning for all benzodiazepines describing the risks of misuse
and abuse, dependence, withdrawal, addiction, and overdose, and the need for(b) (5)
gradual dose tapering. Suggested language is included as an example below,(b) (4), (b) (5)3. Issue a DSC to accompany any labeling changes(b) (5)

4.

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reporting data, understanding that a recently completed DEPI review by Dr. Alex Secora
et. al. [2] would assist with the comparative analysis of alprazolam and otherbenzodiazepines (See Section 1.1). It was also determined that OSE would not be able toaddress Question #2 above due to trivial utilization of Xanax XR relative to Xanax andthe difficulty reliably distinguishing Xanax XR from immediate-release Xanax inepidemiologic databases.
BACKGROUND
The purpose of this review is to inform potential class labeling changes for(b) (5)benzodiazepines
related to this drug class. The
review objectives are:
• To describe the current scope, trends, and patterns of benzodiazepine prescribing,misuse, abuse, and morbidity and mortality in the U.S.
• To stratify outcomes by the involvement of benzodiazepines alone vs.
concomitantly with opioids and other substances (e.g., alcohol, marijuana,
stimulants).
• To review published epidemiologic studies on the risks of abuse, misuse,
addiction, dependence, and overdose associated with long-term use of
benzodiazepines, as well as to identify potential predictors of long-term use anddependence.
• To identify vulnerable populations and risk factors for misuse, abuse, dependence,
addiction, and overdose.
• To provide a high-level overview of all reports of benzodiazepine abuse,dependence, or withdrawal received in FAERS, including distribution by age, sex,
outcome, geographic location, and frequency of AEs reported.
• To conduct a report-level analysis of direct reports of benzodiazepine abuse,dependence, or withdrawal retrieved from FAERS in order to describe
characteristics of these cases in more detail, including time to onset of
dependence, duration of use, as well as reported duration and specific symptoms
of withdrawal.
Previous Review of Postmarketing Data on Benzodiazepines
DEPI completed a review in June 2019, providing postmarketing data on the utilization
and abuse of alprazolam and other commonly prescribed benzodiazepines. Specifically,
DEPI accessed proprietary drug utilization databases available to the FDA, as well as
data on calls to U.S. poison control centers (PCC) and emergency department (ED) visits
due to pharmaceutical drug exposures. DEPI also reviewed the published literature on
alprazolam abuse and associated mortality. In brief, the review concluded that the totalityof epidemiologic data suggested that the public health burden from alprazolam misuse
and abuse and associated morbidity and mortality was substantially greater than fromother benzodiazepines. After adjusting for prescription availability (tablets dispensed),alprazolam’s higher rates of abuse and related adverse outcomes persisted in some, but
not other data sources. The availability of counterfeit alprazolam products further
complicated direct comparisons of abuse rates across benzodiazepine drugs. Abuse and15
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related adverse outcomes were also widely observed with other benzodiazepines, and thereview recommended a comprehensive review of abuse and related outcomes for the(b)entire benzodiazepine class. This review also noted that more than (4) % of alprazolam
prescriptions dispensed were for the immediate release formulation. Therefore, analysesof abuse-related data were not stratified by immediate-release versus extended-releasealprazolam products, even in the few data systems that collect data at the product level, as
these comparisons would not be interpretable.
DPV conducted a search of FAERS and completed a pharmacovigilance memorandum in
January 2018 in response to an observed increase in benzodiazepine AE reports
submitted by patients describing prolonged symptoms after benzodiazepine withdrawal
and failed attempts at discontinuation of benzodiazepines [3]. DPV found that thisincrease in reporting was likely due to an online call to action by the Benzodiazepine
Information Coalition soliciting all patients injured by benzodiazepines to report theirexperiences to the FDA. However, DPV also identified several themes in the FAERS
reports, including: lack of physician education/knowledge regarding benzodiazepine
prescribing, lack of patient education by the physician at the time of prescribing, or aprescribed tapering schedule that did not prevent withdrawal symptoms (i.e. taper was too
rapid). DPV reviewed the product labeling of benzodiazepines in conjunction withwriting this memo and found that, although inconsistent across drugs, they did adequately
convey the risks of abrupt discontinuation of benzodiazepines. Based on analysis of the
FAERS reports and medical literature at the time of this memo, DPV did not recommend
regulatory action.
REGULATORY HISTORY AND PHARMACOLOGY
The first U.S. approval of a benzodiazepine occurred in 1960 for chlordiazepoxide,
followed by diazepam in 1963. Since then, more than a dozen other benzodiazepine
molecules, in multiple formulations, have been approved for use in the U.S. All are
currently classified as schedule IV drugs under the CSA (Table 1.1). Indications for thesebenzodiazepines include anxiety and panic disorder, seizure disorder, insomnia, andsedation. The exact mechanism of action for benzodiazepine is unknown but it ispresumed that binding occurs at several stereospecific receptor sites within the central
nervous system (CNS), specifically enhancing the activity of gamma-aminobutyric acid.
CNS depression occurs with all benzodiazepines [4].

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Table 1.3. Comparison of Benzodiazepine Product Labeling of Abuse, Misuse, Dependence, and Withdrawal
Product InfoWARNINGS

PRECAUTIONSGeneral‡ Physical and Dependence andWithdrawal Information General DRUG ABUSE AR PostD&A MG
Psychological Withdrawal
Symptoms for PatientsAND
introduction(Y/N)
Dependence Reactions,
DEPENDENCE
reports or
Including Seizures
6.2 PMEDrug

RLD or RS
Product(A)NDA(Applicant)Alprazolam*Xanax
N018276(Pharmacia
and Upjohn)X(Additional section
on Interdose
Symptoms and Riskof Dose Reduction)

Alprazolam XR

Xanax XR
N021434(Pharmacia
and Upjohn)

X

X(Additional
section on
Advice for
Panic
Disorder)X

Chlordiazepoxide Librium
X
A085475(RS Valeant)X

X

Clobazam(PLR format)†

Onfi
N202067(RS
Lundbeck)

X
(5.6)

X
(5.4)

Clonazepam*

Klonopin
N017533(Genentech)

X

X

Diazepam*Valium
N013263(Roche)Estazolam

ProsomX
A074921(RS Mayne
Pharma LLC)

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Other Sections

X

X

X

X

hypomania,
mania

X

Y

hypomania,
mania

X

Y

X

X

Y

X

Y

X

X
X
(focus on
seizure
risk)

Y

X

X

Y

X

Y

Table 1.3. Comparison of Benzodiazepine Product Labeling of Abuse, Misuse, Dependence, and Withdrawal
Product InfoWARNINGS

PRECAUTIONSOther Sections

Drug

RLD or RS
Product(A)NDA(Applicant)General‡ Physical and Dependence andWithdrawal Information General DRUG ABUSE AR PostD&A MG
Psychological Withdrawal
Symptoms for PatientsAND
introduction(Y/N)
Dependence Reactions,
DEPENDENCE
reports or
Including Seizures
6.2 PME

Lorazepam*

AtivanN17794(Bausch)X

OxazepamOxazepamA072253(RS Actavis)

Quazepam(PLR format)†

Doral
X
N018708(W/P)(Galt Pharms)

Temazepam

RestorilN018163(SPECGX
LLC)

Triazolam(PLR format)†

HalcionN017892(Pharmacia
and Upjohn)

X

X

Y

X

X

Y

X
(5.3)

X

X
(5.8 Tolerance/
Withdrawal
Phenomena)

X
(9)

Y

X

Y

X
(9)

Y

*Top 4 reported benzodiazepines in FAERS as of June 30, 2019
† In the PLR format, benzodiazepine withdrawal syndrome is in W/P‡“X” in the General column denotes there is no specifically named section for abuse, misuse, dependence or withdrawal in the Warnings section, but there is some mention of these events inan unstructured manner in that same section
Note: Midazolam excluded because not for outpatient use
AR = Adverse Reactions; D&A = Dosage and Administration; MG = Medication Guide; PLR = Physician’s Labeling Rule; PME = Postmarketing Experience; RLD = Reference label drug;
RS = Reference standard; W/P = Warnings and Precautions

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The most prominent warning in the product labeling for all benzodiazepines is a Boxed
Warning for the risks of using benzodiazepines with opioids that may result in profoundsedation, respiratory depression, coma, and death. As summarized in Table 1.3, there isvariable language describing risks of dependence and withdrawal signs and symptoms in
the Warnings Section of all benzodiazepines, except for diazepam, estazolam, andtemazepam, which contain such language in the Drug Abuse and Dependence Section
only. Lorazepam and oxazepam are the only two benzodiazepines that do not have a
Drug Abuse and Dependence Section in their respective product labeling.
We note that the Drug Abuse and Dependence Section of the Xanax product labelingwarns of the risk of withdrawal in patients taking high doses and with longer duration oftreatment, as well as those who received “brief therapy with Xanax at doses within therecommended range for the treatment of anxiety.” While the labeling identifies risk
factors for psychological dependence including patients with history of alcohol or drug
abuse, or “addiction-prone individuals” who should be under careful surveillance when
receiving Xanax, it also recommends that “all patients on XANAX who require a dosage
reduction be gradually tapered under close supervision,” not only those with theaforementioned risk factors.
The Dosage and Administration Section of the Xanax product labeling includes detailed
instructions on how to initiate and discontinue alprazolam. It also includes a warning to
avoid abrupt discontinuation of treatment due to the danger of withdrawal. It further
recommends that “dosage should be reduced gradually when discontinuing therapy or whendecreasing the daily dosage” for all patients.
See below for additional language related to recommended dosage and administration,dose reduction, and warnings for abuse, misuse, dependence, and withdrawal in thelabeling for Xanax as an example [7]. As noted above, this language is not consistentacross all benzodiazepine product labels.
Selected Sections from the Xanax Product Labeling

WARNINGS
Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including XANAX, and opioids may result in
profound sedation, respiratory depression, coma, and death. Because of these risks,

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reserve concomitant prescribing of these drugs for use in patients for whom alternative
treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics andbenzodiazepines increases the risk of drug-related mortality compared to use of opioids
alone. If a decision is made to prescribe XANAX concomitantly with opioids, prescribe
the lowest effective dosages and minimum durations of concomitant use, and follow
patients closely for signs and symptoms of respiratory depression and sedation. In
patients already receiving an opioid analgesic, prescribe a lower initial dose of XANAX
than indicated in the absence of an opioid and titrate based on clinical response. If an
opioid is initiated in a patient already taking XANAX, prescribe a lower initial dose of
the opioid and titrate based upon clinical response.
Advise both patients and caregivers about the risks of respiratory depression and sedation
when XANAX is used with opioids. Advise patients not to drive or operate heavymachinery until the effects of concomitant use with the opioid have been determined [seeDrug Interactions].
Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical events, some life-threatening, are a direct consequence ofphysical dependence to XANAX. These include a spectrum of withdrawal symptoms; themost important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after
relatively short-term use at the doses recommended for the treatment of transient anxiety
and anxiety disorder (ie, 0.75 to 4.0 mg per day), there is some risk of dependence.
Spontaneous reporting system data suggest that the risk of dependence and its severity
appear to be greater in patients treated with doses greater than 4 mg/day and for long
periods (more than 12 weeks). However, in a controlled postmarketing discontinuation
study of panic disorder patients, the duration of treatment (3 months compared to 6
months) had no effect on the ability of patients to taper to zero dose. In contrast, patientstreated with doses of XANAX greater than 4 mg/day had more difficulty tapering to zerodose than those treated with less than 4 mg/day.
The importance of dose and the risks of XANAX as a treatment for panic disorder:
Because the management of panic disorder often requires the use of average daily dosesof XANAX above 4 mg, the risk of dependence among panic disorder patients may behigher than that among those treated for less severe anxiety. Experience in randomized
placebo-controlled discontinuation studies of patients with panic disorder showed a highrate of rebound and withdrawal symptoms in patients treated with XANAX compared toplacebo-treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic of panic
disorder (primarily panic attacks) to levels approximately equal to those seen at baseline
before active treatment was initiated. Rebound refers to a return of symptoms of panic
disorder to a level substantially greater in frequency, or more severe in intensity than seen
at baseline. Withdrawal symptoms were identified as those which were generally not
characteristic of panic disorder and which occurred for the first time more frequently
during discontinuation than at baseline.

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Interdose Symptoms
Early morning anxiety and emergence of anxiety symptoms between doses of XANAX
have been reported in patients with panic disorder taking prescribed maintenance doses of
XANAX. These symptoms may reflect the development of tolerance or a time interval
between doses which is longer than the duration of clinical action of the administereddose. In either case, it is presumed that the prescribed dose is not sufficient to maintainplasma levels above those needed to prevent relapse, rebound or withdrawal symptoms
over the entire course of the interdosing interval. In these situations, it is recommended
that the same total daily dose be given divided as more frequent administrations (seeDOSAGE AND ADMINISTRATION).
Risk of Dose Reduction
Withdrawal reactions may occur when dosage reduction occurs for any reason. This
includes purposeful tapering, but also inadvertent reduction of dose (eg, the patient
forgets, the patient is admitted to a hospital). Therefore, the dosage of XANAX should be
reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION).
PRECAUTION
Information for Patients
For all users of XANAX:To assure safe and effective use of benzodiazepines, all patients prescribed XANAX
should be provided with the following guidance.
1. Advise both patients and caregivers about the risks of potentially fatal respiratory
depression and sedation when XANAX is used with opioids and not to use such drugs
concomitantly unless supervised by a health care provider.
2. Advise patients not to drive or operate heavy machinery until the effects ofconcomitant use with the opioid have been determined [see Drug Interactions].
3. Inform your physician about any alcohol consumption and medicine you are taking
now, including medication you may buy without a prescription. Alcohol should
generally not be used during treatment with benzodiazepines.
4. Not recommended for use in pregnancy. Therefore, inform your physician if you are
pregnant, if you are planning to have a child, or if you become pregnant while you aretaking this medication.
5. Inform your physician if you are nursing.
6. Until you experience how this medication affects you, do not drive a car or operatepotentially dangerous machinery, etc.
7. Do not increase the dose even if you think the medication "does not work anymore"
without consulting your physician. Benzodiazepines, even when used asrecommended, may produce emotional and/or physical dependence.
8. Do not stop taking this medication abruptly or decrease the dose without consulting
your physician, since withdrawal symptoms can occur.
Additional advice for panic disorder patients:
The use of XANAX at doses greater than 4 mg/day, often necessary to treat panic
disorder, is accompanied by risks that you need to carefully consider. When used at doses
greater than 4 mg/day, which may or may not be required for your treatment, XANAX

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has the potential to cause severe emotional and physical dependence in some patients andthese patients may find it exceedingly difficult to terminate treatment. In two controlled
trials of 6 to 8 weeks duration where the ability of patients to discontinue medication wasmeasured, 7 to 29% of patients treated with XANAX did not completely taper off
therapy. In a controlled postmarketing discontinuation study of panic disorder patients,
the patients treated with doses of XANAX greater than 4 mg/day had more difficulty
tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it isimportant that your physician help you discontinue this medication in a careful and safemanner to avoid overly extended use of XANAX.
In addition, the extended use at doses greater than 4 mg/day appears to increase theincidence and severity of withdrawal reactions when XANAX is discontinued. These are
generally minor but seizure can occur, especially if you reduce the dose too rapidly or
discontinue the medication abruptly. Seizure can be life-threatening.
ADVERSE REACTIONS
To discontinue treatment in patients taking XANAX, the dosage should be reduced
slowly in keeping with good medical practice. It is suggested that the daily dosage of
XANAX be decreased by no more than 0.5 mg every three days (see DOSAGE AND
ADMINISTRATION). Some patients may benefit from an even slower dosage reduction.
In a controlled postmarketing discontinuation study of panic disorder patients which
compared this recommended taper schedule with a slower taper schedule, no difference
was observed between the groups in the proportion of patients who tapered to zero dose;
however, the slower schedule was associated with a reduction in symptoms associatedwith a withdrawal syndrome.
As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle
spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such asagitation, rage, irritability, and aggressive or hostile behavior have been reported rarely.
In many of the spontaneous case reports of adverse behavioral effects, patients werereceiving other CNS drugs concomitantly and/or were described as having underlying
psychiatric conditions. Should any of the above events occur, alprazolam should be
discontinued. Isolated published reports involving small numbers of patients havesuggested that patients who have borderline personality disorder, a prior history ofviolent or aggressive behavior, or alcohol or substance abuse may be at risk for such
events. Instances of irritability, hostility, and intrusive thoughts have been reported
during discontinuation of alprazolam in patients with posttraumatic stress disorder.
DRUG ABUSE AND DEPENDENCE
Physical and Psychological Dependence
Withdrawal symptoms similar in character to those noted with sedative/hypnotics andalcohol have occurred following discontinuance of benzodiazepines, including XANAX.
The symptoms can range from mild dysphoria and insomnia to a major syndrome that
may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions.
Distinguishing between withdrawal emergent signs and symptoms and the recurrence of
illness is often difficult in patients undergoing dose reduction. The long term strategy fortreatment of these phenomena will vary with their cause and the therapeutic goal. When

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necessary, immediate management of withdrawal symptoms requires re-institution oftreatment at doses of XANAX sufficient to suppress symptoms. There have been reports
of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These
failures have been attributed to incomplete cross-tolerance but may also reflect the use of
an inadequate dosing regimen of the substituted benzodiazepine or the effects ofconcomitant medications.
While it is difficult to distinguish withdrawal and recurrence for certain patients, the timecourse and the nature of the symptoms may be helpful. A withdrawal syndrome typically
includes the occurrence of new symptoms, tends to appear toward the end of taper or
shortly after discontinuation, and will decrease with time. In recurring panic disorder,
symptoms similar to those observed before treatment may recur either early or late, andthey will persist.
While the severity and incidence of withdrawal phenomena appear to be related to doseand duration of treatment, withdrawal symptoms, including seizures, have been reported
after only brief therapy with XANAX at doses within the recommended range for thetreatment of anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often
more prominent after rapid decrease of dosage or abrupt discontinuance. The risk ofwithdrawal seizures may be increased at doses above 4 mg/day (see WARNINGS).
Patients, especially individuals with a history of seizures or epilepsy, should not be
abruptly discontinued from any CNS depressant agent, including XANAX. It is
recommended that all patients on XANAX who require a dosage reduction be graduallytapered under close supervision (see WARNINGS and DOSAGE AND
ADMINISTRATION).
Psychological dependence is a risk with all benzodiazepines, including XANAX. The
risk of psychological dependence may also be increased at doses greater than 4 mg/day
and with longer term use, and this risk is further increased in patients with a history ofalcohol or drug abuse. Some patients have experienced considerable difficulty in taperingand discontinuing from XANAX, especially those receiving higher doses for extended
periods. Addiction-prone individuals should be under careful surveillance when receiving
XANAX. As with all anxiolytics, repeat prescriptions should be limited to those who areunder medical supervision.
DOSAGE AND ADMINISTRATION
The lowest possible effective dose should be employed and the need for continued
treatment reassessed frequently. The risk of dependence may increase with dose andduration of treatment.
In all patients, dosage should be reduced gradually when discontinuing therapy or whendecreasing the daily dosage. Although there are no systematically collected data to
support a specific discontinuation schedule, it is suggested that the daily dosage be
decreased by no more than 0.5 mg every 3 days. Some patients may require an evenslower dosage reduction.
Dose Titration
Generally, therapy should be initiated at a low dose to minimize the risk of adverse
responses in patients especially sensitive to the drug. Dose should be advanced until an

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acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic
attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.
Dose Reduction
Because of the danger of withdrawal, abrupt discontinuation of treatment should be
avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).
In all patients, dosage should be reduced gradually when discontinuing therapy or whendecreasing the daily dosage. Although there are no systematically collected data to
support a specific discontinuation schedule, it is suggested that the daily dosage be
decreased by no more than 0.5 mg every three days. Some patients may require an evenslower dosage reduction.
In any case, reduction of dose must be undertaken under close supervision and must be
gradual. If significant withdrawal symptoms develop, the previous dosing scheduleshould be reinstituted and, only after stabilization, should a less rapid schedule ofdiscontinuation be attempted. In a controlled postmarketing discontinuation study ofpanic disorder patients which compared this recommended taper schedule with a slower
taper schedule, no difference was observed between the groups in the proportion ofpatients who tapered to zero dose; however, the slower schedule was associated with areduction in symptoms associated with a withdrawal syndrome. It is suggested that thedose be reduced by no more than 0.5 mg every 3 days, with the understanding that somepatients may benefit from an even more gradual discontinuation. Some patients may
prove resistant to all discontinuation regimens.
2

REVIEW METHODS AND MATERIALSOVERVIEW AND FRAMEWORKIn this integrated review, pharmacovigilance data and epidemiologic data werecomplementary for understanding the risks from benzodiazepine misuse, abuse, anddependence. Furthermore, drug utilization data provided context. We examined several
data sources to describe the utilization, abuse, misuse, and related adverse outcomes,
associated with benzodiazepines. These data sources collect information from various
populations: the general population, people filling prescriptions in the outpatient retailsetting, people seeking medical treatment for adverse effects of non-medical use, andindividuals entering or being assessed for substance use disorder (SUD) treatment. We
present major features of each data source in Table 2.1. We provide a more detailed
description of each data source and our analytic approach in the sections below. Unlessotherwise indicated, we used standard regulatory definitions of misuse and abuse. [8]Misuse: Intentional use, for therapeutic purposes, of a drug in a way other thanprescribed or by an individual for whom it was not prescribed
Abuse: the intentional, non-therapeutic use of a drug product or substance, even once,
for its desirable psychological or physiological effects

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Table 2.1 Overview of data sources to assess the current landscape of benzodiazepines misuse, abuse, dependence, andwithdrawal.
Characteristic
Population and data sources used
Use of data source(s)assessed
Drug Utilization

The IQVIA, National Sales
Perspectives™ (NSP) database, 2018

Estimated number of benzodiazepine units from manufacturers to all
U.S. channels of distribution

The IQVIA, National Prescription
Audit™ (NPA) database, 2014-2018

Estimated number of prescriptions and tablets dispensed from outpatient
retail/mail order pharmacies

The IQVIA, Total Patient Tracker™
(TPT) database, 2014-2018

Estimated number of unique patients, stratified by molecule, and age
groups who received prescriptions dispensed from outpatient retailpharmacies
Determined utilization patterns by duration of use estimated fromdispensed prescription claims data from retail pharmacies

The Symphony Health Integrated
Dataverse (IDV), 2015-2018
Scale and relative
frequency of
benzodiazepine
misuse, abuse,dependence, andwithdrawal
Routes of abuse
forbenzodiazepines
Morbidity andmortality
associated withbenzodiazepine
misuse, abuse,

General population
National Survey on Drug Use and
Health (NSDUH), 2015-2018
Secondary school students
Monitoring The Future (MTF), 20072018
Calls for advice after misuse/abuse
National Poison Data System(NPDS) exposure calls to Poison
Control Center (PCC), 2009-2017
People seeking care for adverse
effects of pharmaceutical exposures
National Electronic Injury
Surveillance System – Cooperative
Adverse Drug Event Surveillance
Project (NEISS-CADES), 2016-2017

Estimated number of individuals in the general U.S. population reporting
misuse or abuse of benzodiazepines
Estimated number of students in U.S. secondary schools reporting misuseor abuse of benzodiazepines
Routes of abuse for single-substance exposure calls

Assess outcomes such as need for healthcare intervention associated withbenzodiazepine misuse and abuse

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Characteristic
assessed

Population and data sources used

Use of data source(s)dependence, andwithdrawal

Calls for medical assistance after
pharmaceutical exposures
NPDS exposure calls to PCCs,
2009-2017: benzodiazepines
Drug overdose deaths
National Vital Statistics System,
Mortality (NVSS-M), 2000-2017

Quantify calls involving benzodiazepine misuse or abuse
Assess severity of medical outcomes for drug exposures from calls to
PCCs by specific benzodiazepines

General population, prescribers, andpatients
FAERS, All reports through June 30,
2019

Described characteristics of and outcomes involved in benzodiazepine
reports of drug abuse, dependence, and withdrawal

Occurrence of
Sedative,
Hypnotic, orAnxiolytic Use
Disorder related
to benzodiazepine
usePeople entering treatment for
substance use disorder (SUD)
Treatment Episode Data Set (TEDS),
2017

Proportion of admissions for treatment for SUD in which patientsendorse benzodiazepines as primary, secondary, and tertiary drugs ofabuse

General population
National Survey on Drug Use and
Health (NSDUH), 2015-2016(published analysis of NSDUH [9])Longitudinal risk
and risk factors
forbenzodiazepine
misuse, abuse,
addiction,
dependence, andlong-term use

PubMed, Embase and Web of
Science databases, 2000-2009

Estimated number of individuals in the general U.S. population who
reported misuse or abuse of benzodiazepines, did not report misuse orabuse of other sedatives, hypnotics, or anxiolytics, and met the criteria
for Sedative, Hypnotic, or Anxiolytic Use Disorder, per Diagnostic andStatistical Manual of Mental Disorders, 4th Edition
Conducted literature search for• Longitudinal studies of the risk of misuse, abuse, addiction, anddependence from benzodiazepine use• Studies of factors associated with benzodiazepine dependence orlong-term use;
• Studies of social factors affecting preferences and patterns ofabuse and misuse of specific benzodiazepine products

Mortality
associated withbenzodiazepine
use

Assessed deaths involving benzodiazepines, by decedent characteristics
and co-involved drug substances

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DRUG UTILIZATION ANALYSES
Proprietary drug utilization databases available to the Agency were used to conduct theseanalyses; see Appendix A.2 for detailed descriptions and limitations of the databases.
The focus of this analysis is on oral formulations of benzodiazepines, unless otherwise
noted. Also, different analyses had differing age groups or time frames studied based on
factors such as database capabilities and limitations.
To determine the various settings of care where benzodiazepines are distributed, the
IQVIA, National Sales Perspectives™ (NSP) database was used to obtain the estimatednumber of benzodiazepine units (e.g., number of tablets, milliliters of liquid) sold frommanufacturers to U.S. retail and non-retail channels of distribution in 2018. The sales
distribution data do not necessarily reflect what is being directly sold or administered topatients; rather, these data provide an estimate of units sold from the manufacturers into
various channels of distribution.
The IQVIA, National Prescription Audit™ (NPA) database was used to obtain thenationally estimated number of prescriptions and tablets dispensed from U.S. outpatient
retail/mail order pharmacies for oral benzodiazepines from January 2014 throughDecember 2018, annually. In addition, the NPA Extended Insights (NPA EI) and New to
Brand (NPA NTB) databases was used to estimate the number of prescriptions andtablets dispensed stratified by age groups (0-9,10-19,20-39,40-64,65+), formulation, andgender.
The IQVIA, Total Patient Tracker™ (TPT) database was used to obtain the estimatednumber of unique patients, stratified by molecule, and age groups (0-11,12-17,18-25,2639,40-64,65+) who received a dispensed prescription for oral benzodiazepines from U.S.
outpatient retail pharmacies, from 2014 through 2018, annually.
The Symphony Health Integrated Dataverse® (IDV) was used to determine U.S. estimatesof utilization patterns by duration of use for top benzodiazepines, stratified by age groups(0-11,12-17,18-25,26-39,40-64,65+), annually from 2015 through 2018. Duration was
calculated using the days’ supply values for prescription dispensings, typically entered bydispensing pharmacy staff. Episodes of therapy were created using an allowable gap of
50% of the previous dispensing’s days’ supply to link to a subsequent dispensing. For
example, a dispensing for a 30-day supply was allowed an extra 15 days from thedispensing end date to link to the next dispensing.
THE NATIONAL SURVEY ON DRUG USE AND HEALTHNSDUH is an annual survey funded by the Substance Abuse and Mental Health Services
Administration (SAMHSA) designed to provide nationally representative estimates ofillicit and prescription drug misuse/abuse in the general U.S. population: noninstitutionalized residents of the U.S. who are aged 12 years and above. Population
subgroups not covered by the survey include individuals residing within institutional
facilities (e.g., jails, nursing homes), as well as those without a permanent address (e.g.,homeless individuals). The survey is conducted in a face-to-face manner, and during theyear 2018, the interview final response rate was 66.5% for a total of 67,791 completedinterviews [10].

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Since 2015, NSDUH has elicited information on any use of benzodiazepines, as well as
misuse/abuse, in the past year. NSDUH defines misuse of a drug as the following: “use in
any way not directed by a doctor, including use without a prescription of one’s own; usein greater amounts, more often, or longer than told.” Since NSDUH’s definition of
misuse includes intentional, non-therapeutic use of a drug to obtain a desired
psychological or physiological effect (i.e., abuse), this review labels it misuse or abuse.
NSDUH defines “any use of benzodiazepines” as any use of benzodiazepines for any
reason, either use of one’s own prescription benzodiazepine as directed by a physician, or
misuse or abuse.
We extracted available data from reports and detailed tables from the 2016-2018 NSDUH
posted publicly on the SAMHSA website [11]. We reported national estimates in terms ofnumbers of individuals, percent of the total population, and percent of past-year anyusers. To give some context to the estimates of misuse or abuse of benzodiazepines, we
also extracted the corresponding estimates for misuse or abuse of prescription pain
relievers and prescription stimulants, respectively. Also, we abstracted statistics on the
primary reason for benzodiazepine misuse or abuse and on the prevalence of past-year
benzodiazepine use disorder 2, from a peer-reviewed publication of an analysis of 20152016 NSDUH data [9], written by personnel from the National Institute of Drug Abuse
and SAMHSA.
MONITORING THE FUTURE
Supported by the National Institute on Drug Abuse (NIDA) and conducted by the
University of Michigan, MTF is a nationally representative, annual cross-sectional surveyof adolescent, college, and adult high school students and graduates, intended to monitor
emerging substance abuse problems and understand the effectiveness of policy andintervention efforts designed to address the. The survey captures self-reported
information on drug use behaviors among students in the 8th, 10th, and 12th grades, andhas been conducted continuously since 1975. This school-based survey asks about use ofa wide variety of substances, including alcohol, tobacco, and other over-the-counter,prescription, and illicit drugs. Specifically, the survey asks about nonmedical use of
several stimulants and other prescription drugs, that is, use “not under a doctor’s orders.”
Results reported in this review are from the 2018 report [12]. Trends in specifictranquilizers and sedatives are determined by branching questions in the 12th grade
questionnaire. Questions about the use of specific drugs are not asked of 8th and 10th
graders. Twelfth grade respondents are asked to report use of a general type of drug suchas sedative or tranquilizer in the last 12 months. For those indicating the use of a general
type of drug, they are given follow-up questions, including “what tranquilizer have you
taken during the last year without a doctor’s orders? (Mark all that apply.)” Because
endorsing a benzodiazepine in response to this question may indicate misuse or abuse, as
FDA defines them, this review labels it misuse or abuse.

2

The study classified participants as meeting criteria for benzodiazepine use disorder if they reported
misuse or abuse of benzodiazepines, did not report misuse or abuse of other sedatives, hypnotics, or
anxiolytics, and met the criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder, per DSM-IV.

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We report results from 2007-2018, however, as seldom-used drugs were dropped andmore commonly used drugs were added, not all years are available for all drugs. It is also
important to note that the survey structure requires the individual to indicate that they
misused or abused a sedative or tranquilizer before they are provided the option of theindividual benzodiazepines; some individuals may not be aware that the benzodiazepine
they misused or abused is contained under these general classes. Additionally, we areunable to report overall benzodiazepine misuse and abuse since this question is not asked
and because the selected benzodiazepines in this survey are included among other nonbenzodiazepines within larger classes of drugs.
AMERICAN ASSOCIATION OF POISON CONTROL CENTERS, NATIONAL POISONDATA SYSTEM
Data Source
NPDS is a database managed by the American Association of Poison Control Centers(AAPCC), and derived from a nationwide network of PCCs that receive calls fromindividuals, healthcare professionals, and other interested persons in the general U.S.
popoulation regarding exposures to prescription drugs and other substances. [13] PCC
healthcare professionals systematically follow up on reported exposures to document
their medical outcome. Quality control measures are used to ensure data accuracy andcompleteness. Note that exposures do not necessarily represent a poisoning or overdose,as the AAPCC does not completely verify the accuracy of every report made to member
centers. Additional exposures may go unreported to PCCs. [13]In 2017, there were over 2.6 million calls to PCCs, the majority of which (2.1 million)
were human exposure calls. Of these human exposure calls, 60% were for individuals
under the age of 20. Almost 19% were for intentional exposures, and the remainder forother reasons (e.g., adverse reaction, withdrawal).
Data Analysis
We searched NPDS for closed cases of human exposure to benzodiazepines, 2009-2017,by using the AAPCC generic code for benzodiazepines and excluding cases that had
medical outcome classified as “confirmed non-exposure.” We identified the generic codefor benzodiazepines using MicroMedex® Solutions and the 2019 AAPCC Pharmaceuticaland Non-Pharmaceutical Generic Code List – February 2019 version (See Appendix B
Table B1). At the time of extraction, AAPCC had completed its standard processes foroutcome adjudication and quality control for all these data and had locked the data toensure reliability.
Using these data, we conducted further analysis on selected cases from 2013-2017 with
reported exposure to one of five, commonly prescribed benzodiazepine molecules:
alprazolam, clonazepam, diazepam, lorazepam, and temazepam. We used MicroMedex®
product codes to identify these cases. (Product codes are included in Appendix B Table
B2.)
Search parameters used for benzodiazepines and selected benzodiazepine molecules are
summarized in Table 2.2.

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Table 2.2. NPDS Search parameters- benzodiazepines
Report nameCase Log (Generic Code)Month/year of query
8/2019Date range for query
1/1/2009- 12/31/2017(benzodiazepines)
Date range for query
1/1/2013- 12/31/2017(selected benzodiazepines:
alprazolam, clonazepam,
diazepam, lorazepam, andtemazepam)
Call type
Exposure
Case status
ClosedSpecies
Human
Minimum Age
0 (years)

Analysis of NPDS consisted of three components:
1. Trends in exposure calls, 2009-2017
Data were stratified by reason of exposure (intentional: abuse, misuse, suicide, unknown;
unintentional: adverse reaction, withdrawal, unknown; and other) and severity of related
medical outcomes (minor effect, moderate effect, major effect, and death). A sub-analysis
was conducted for abuse/misuse calls to examine the number of calls, stratified by single
and multiple-substance.
2. Reason for exposure by age group
Data were aggregated for the nine-year period and stratified by age group (0-5, 6-12, 1319, 20-39, 40-64, 65 and older, and unknown).
3. Cases of abuse and misuse
We analyzed data from calls involving exposure to benzodiazepines that had beenclassified as either of two, mutually exclusive AAPCC categories for reason for
exposure: “intentional abuse” or “intentional misuse.” We evaluated the calls using
categories defined by AAPCC (variable definitions are included in Appendix B Table
B3).
a. Co-exposures: prescription opioids, heroin/illicit fentanyl analogue, alcohol,
marijuana, and stimulants (both prescription and illicit)
b. Route of abuse/misuse: oral, nasal/inhalation, injection, other, and unknown.
In the NPDS data, multiple routes can be reported for a single substance. For
these cases, we counted each route mentioned by the caller separately. As aresult, the totals for each individual route may exceed the total number of
exposures for that product. Also, route of administration cannot be mapped toa specific drug in multiple-substance exposures.
c. Severity of medical outcomes for cases with related clinical effects:
i. All abuse/misuse cases

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Specific multiple-cause-of-death codes identified the drug categories involved inoverdose deaths. Benzodiazepines were uniquely identified by the ICD-10 code T42.4.
Other drugs involved were identified through multiple-cause-of-death ICD-10 codes
T36.0 to T50.9. Of note, the ICD-10 codes, T36.0 to T50.9, do not include alcohol. We
stratified drug overdose deaths by alcohol involvement, which was defined using the
ICD-10 code T51.0 (“ethanol”), a sub-category of T51 (“toxic effect of alcohol”).
Prescription opioids were defined using the conservative definition proposed by Seth, etal. [26] (ICD-10: T40.2 to T40.3). Synthetic opioids were defined using the ICD-10 code
T40.4. Heroin was defined using the ICD-10 code T40.1. Stimulants were defined using
the ICD-10 code T43.6 (“psychostimulants with abuse potential”).
Table 2.4. Underlying Cause of Death and Multiple Cause of Death ICD-10 codes
Category
ICD-10 code
Underlying Cause of Death
Drug Poisoning (overdose) a
Unintentional
X40-X44
Intentional/ suicide
X60-X64
Homicide
X85
Undetermined
Y10-Y14
Multiple Cause of Death
Poisoning by drugs, medicaments and biological
T36.0 to T50.9
substances b
Benzodiazepine
T42.4
Prescription opioids c
T40.2 to T40.3
Other opioids
T40.2
Methadone
T40.3
Synthetic opioids
T40.4
HeroinT40.1
Stimulants (psychostimulants with abuse
T43.6
potential)
Alcohol (ethanol)
T51.0
Source: CDC WONDER. Multiple Cause of Death (Detailed Mortality) www.wonder.cdc.gov [22]aUnderlying cause of death, drug poisonings [25]bDoes not include alcohol (ICD-10: T51.0)cConservative definition according to Seth et al (2018) [26]

LITERATURE REVIEW
We conducted two literature searches for this review.
We focused the first literature search on identifying longitudinal studies evaluating therisk of misuse, abuse, dependence, and addiction as outcomes of long-term
benzodiazepine use and studies examining predictors of long-term benzodiazepine use or
benzodiazepine dependence. We created search strings individualized for the PubMed,
Embase and Web of Science databases and conducted these database searches on July 26,
2019 and July 30, 2019. Search strings for each database are included in Appendix E
Table E1. Briefly, search strings selected articles with benzodiazepine or a specific35
Reference ID: 4675389

benzodiazepine molecule in the title; abuse, misuse or dependence related terminology;
and epidemiologic study designs, especially longitudinal cohorts or studies involving
follow-up time. The search string excluded articles with terminology indicating clinical,
laboratory or animal study designs. We selected articles for a full-text screen by firstreading titles and abstracts. Based on the full-text screen, we included articles in thereview if they described the risk of misuse, abuse and addiction from long-term
benzodiazepine use and risk factors for benzodiazepine dependence and long-term
benzodiazepine use. Studies reporting on risks of concomitant use of benzodiazepines
with prescription opioids were not considered within the scope of this review since thishad been previously described [27]. We also excluded articles reporting on studies
conducted prior to 2000 and conference abstracts.
We identified 1,688 articles from searching PubMed, Embase, and Web of Science. Afterremoving duplicate articles, 1,152 articles remained for title screening. We then screened
these articles based on information in the title and abstract and 182 articles remained forfull text screening. Finally, 6 articles met our inclusion criteria and were included in thisreview (Appendix F Table F1). The most common reasons why we excluded articles
based on the full-text screen were cohorts which included patients using Z-drug, opioids,or other drugs in addition to benzodiazepines and lack of an assessment of abuse,dependence, or long-term use outcome.
For the second literature search, we identified studies describing social factors associatedwith preferences and patterns of abuse and misuse of benzodiazepines, focusing on
specific benzodiazepine products. This search was conducted on November 13, 2019. For
this search, we searched PubMed, Embase and Web of Science. The search string
selected articles with benzodiazepine or a specific benzodiazepine molecule in the title,quantitative and qualitative epidemiologic studies, terminology for abuse and misuse, andterminology for social influence and behaviors. As with the first literature search, we
excluded articles with terminology indicating clinical, laboratory or animal study designs,
and we excluded conference abstracts. Search strings for this literature search areincluded in Appendix E Table E2.
We identified 129 records from PubMed, Embase, and Web of Science for the second
literature search. After deleting duplicates, 107 articles remained for title and abstract
screening. The majority, 105 articles, were excluded during the title and abstract
screening. The two remaining articles both included qualitative data analysis of youth andyoung adults (Appendix F Table F2).
FDA ADVERSE EVENT REPORTING SYSTEM
Definitions
In addition to the standard regulatory definitions of misuse and abuse in Section 2.1, we
provide additional definitions and examples of drug abuse, misuse, dependence, andwithdrawal for use in the FAERS portion of this review.
Table 2.5 provides definitions for drug abuse, misuse, dependence, and withdrawal.
Table 2.6 provides examples of clinical manifestations associated with abuse, misuse,
and withdrawal of sedatives or anxiolytics, such as benzodiazepines.

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Table 2.5. Definitions and Examples of Drug Abuse, Misuse, Dependence, Tolerance, andWithdrawal in FDA Guidances [28]Definition
Examples• Additional doses to achieve
Intentional, nontherapeutic use of a drug producteuphoria
Drug abuse or substance even once, to achieve a desired• Administration via an
psychological or physiological effectunapproved route•DrugmisuseIntentional therapeutic use of a drug product in an
inappropriate way and specifically excludes thedefinition of abuse••
Physical dependence is a state that develops as aresult of physiological adaptation in response torepeated drug use, manifested by withdrawal
signs and symptoms after abrupt discontinuation
or a significant dose reduction of a drug.
Drug
Psychological dependence is a state in which
dependence individuals have impaired control over drug use
based on the rewarding properties of the drug
(ability to produce positive sensations that
increase the likelihood of drug use) or thepsychological distress produced in the absence ofthe drug.
Tolerance is a state that develops as a result ofphysiological adaptation characterized by areduced response to a specific dose of drug after
Tolerance
repeated administration of the drug (i.e., a higher
dose of a drug is required to produce the same
effect that was once obtained at a lower dose).
Withdrawal is defined as a characteristic
withdrawal syndrome for that drug occurring in
response to 1) abrupt discontinuation or a
Withdrawal
significant dose reduction of that drug or 2)
administration of an antagonist or taking the drug
itself to alleviate withdrawal symptoms.

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Additional dose of pain
medication to alleviate pain
Additional dose of weightloss medication to achieve
greater or faster weight loss
Taking a sleeping pill for
insomnia from a friend•••

Caffeine
Clonidine
Amphetamines•

Opioids••

Opioids
Clonidine••

Opioids
Beta-blockers

Table 2.6. Examples of the Clinical Manifestations Associated with Drug Abuse, Misuse, andWithdrawal [29]Drug Class
Drug Abuse or Misuse
Withdrawal
Sedatives/Anxiolytics
Slurred speech,
Anxiety, insomnia, autonomic(i.e., benzodiazepines) incoordination, unsteadyhyperactivity (e.g., sweating, pulse rate
gait, nystagmus, impaired
greater than 100 beats per minute) handcognition, mood changes,
tremor, transient visual, tactile, or
impaired judgement,
auditory hallucinations or illusions,
impaired memory, stupor, or psychomotor agitation, nausea/vomiting,coma
grand mal seizures
FAERS Search Strategy
DPV conducted two searches of FAERS to retrieve reports of benzodiazepine abuse,dependence, or withdrawal. We used the search strategy in Table 2.7 to provide a highlevel overview of trends in reporting over all time; a report-level analysis was notcompleted on the results of this search.
Table 2.7. FAERS Search Strategy – High-Level Overview*
Date of Search
July 1, 2019
Time Period of Search
All reports through June 30, 2019
Search Type
Drug Safety Analytics Dashboard Quick Search
Product Terms
Product active ingredient: alprazolam; bromazepam; brotizolam;clobazam, chlordiazepam; chlordiazepoxide; chloridazepoxidehydrochloride; clonazepam; clotiazepam; cloxazolam; delorazepam;
diazepam; estazolam; flubromazepam; flubromazolam; flutazolam;loprazolam; loprazolam mesilate; lorazepam; lormetazepam;
medazepam; midazolam hydrochloride; midazolam maleate;
nitrazepam; nitrazolam; nordazepam; oxazepam; phenazepam;
quazepam; temazepam; tetrazepam; triazolam
MedDRA Search Terms Drug abuse dependence and withdrawal (SMQ) Broad search†(Version 22.0)*See Appendix G1 for a description of the FAERS database.
†
See Appendix G2 for a list of the preferred terms (PTs) in Drug abuse dependence and withdrawal (SMQ) BroadsearchMedDRA=Medical Dictionary for Regulatory Activities; SMQ=Standardised MedDRA Query

We used the search strategy in Table 2.8 to target a subset of FAERS reports tocharacterize cases of abuse, dependence, or withdrawal. During DPV’s routine
pharmacovigilance activities, we noted that direct reports provide significant detail withrespect to dependence and withdrawal; therefore, we limited the search strategy in Table
2.8 to direct reports only, i.e., those submitted to the FDA directly from consumers andhealthcare professionals. We further limited these search results to only reports with abenzodiazepine as a single drug substance to prevent confounding by concomitant
medications.

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Table 2.8. FAERS Search Strategy – Benzodiazepine as Single Drug Substance ReportLevel Analysis*
Date of Search
July 1, 2019
Time Period of Search All reports through June 30, 2019
Search Type
Drug Safety Analytics Dashboard Quick Search
Product Terms
Product active ingredient: alprazolam; bromazepam; brotizolam;clobazam, chlordiazepam; chlordiazepoxide; chloridazepoxidehydrochloride; clonazepam; clotiazepam; cloxazolam; delorazepam;
diazepam; estazolam; flubromazepam; flubromazolam; flutazolam;loprazolam; loprazolam mesilate; lorazepam; lormetazepam;
medazepam; midazolam hydrochloride; midazolam maleate; nitrazepam;
nitrazolam; nordazepam; oxazepam; phenazepam; quazepam;
temazepam; tetrazepam; triazolam
MedDRA Search
Drug abuse dependence and withdrawal (SMQ) Narrow search†
Terms(Version 22.0)
Case Type
DirectOther Limitation
A benzodiazepine is the only coded product for the report or mentioned
in the narrative (i.e., single drug substance)* See Appendix G1 for a description of the FAERS database.
†
See Appendix G2 for a list of the preferred terms (PTs) in Drug abuse dependence and withdrawal (SMQ) NarrowsearchMedDRA=Medical Dictionary for Regulatory Activities; SMQ=Standardised MedDRA Query

Case Definition for Report-Level Analysis of Benzodiazepine as Single Drug
Substance [28]We used the following inclusion and exclusion criteria to assess the FAERS reports
retrieved with the search criteria described in Table 2.8.
Inclusion criteria:
Cases that report one or more of the following criteria:•

The term(s) “drug abuse,” “drug misuse,” “drug dependence,” “drug tolerance,” or“drug withdrawal” was stated in the narrative with or without clinical manifestations
associated with drug abuse, misuse, dependence, tolerance, or withdrawal of the drugof interest (see Table 2.6 in Section 2.10.1 for examples specific tosedatives/anxiolytics, e.g. benzodiazepines).
OR•

Clinical assessment by the reviewer of drug abuse or misuse based on the provided
case details (e.g., reported unapproved route of use, drug intake without aprescription, intentionally taking higher than prescribed doses, self-treatment of39
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Table A.7 in Appendix A.1 provides estimates of prescriptions dispensed stratified bymolecule, age and formulation between 2014 and 2018 annually. Of note, the total
number of oral liquid clobazam prescriptions in patients aged 0-9 years was substantiallyhigher than in the adult population.
Table A.8 in Appendix A.1 provides the estimated number of unique patients dispensed
one of the top 6 oral benzodiazepine prescription from outpatient retail pharmacies,
stratified by molecule and age from 2014 through 2018,
annually. Of note, the pediatric(b)
population (ages ≤17 year old) comprised less than (4)% of patients dispensed
benzodiazepines each year over the examined time period.

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Figure 3.8. Abuse/misuse exposure calls involving benzodiazepines, single andmultiple-substances, by year

Severity of medical outcomes for cases with related clinical effects
As shown in Figure 3.9, medical outcomes were generally more severe in benzodiazepine
abuse/misuse calls involving multiple substances than in those involving just the benzodiazepine.
Among single-substance benzodiazepine misuse/abuse exposure calls , minor effect (i.e.,
symptoms that are minimally bothersome to patients and usually resolved rapidly) was the mostcommon category of related medical outcomes (73.1%), followed by moderate effect (i.e.,
symptoms that are prolonged and involved some treatments; 25.1%). In multiple-substance
exposure calls involving abuse/misuse, the proportion of calls with a moderate effect (43.3%) was
similar to the proportion with a minor effect (45.3%) (Figure 3.9; Appendix B Table B5). Moreinformation on medical outcome definition is provided in Appendix B Table B3.

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Figure 3.9 Severity of medical outcomes for abuse/misuse exposure calls with related
clinical effects, by single and multiple-substance, 2013-2017

The distribution of medical outcome severity in single-substance misuse/abuse calls was
similar across the five most commonly prescribed benzodiazepines. Across all fivedrugs, minor effect was the most common medical outcome, ranging between 71.4%80.6%. Moderate effect was the second most common medical outcome, accounting for
approximately one fifth of exposure calls involving abuse/misuse (Figure 3.10).

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Figure 3.10. Medical severity by active pharmaceutical ingredient among single
Substance calls involving abuse or misuse: National Poison Data System, U.S., 20132017

Frequency of related clinical effects in exposures with moderate-to-severe medical
outcomes
As shown in Table 3.6, 15% (n=2,394) of 15,779 single-substance benzodiazepine
exposure calls reported to poison centers specifically involving abuse between 2009-2017
reported moderate-to-severe medical outcomes in patients with clinical effects related tothe exposure.
Table 3.6. Single-substance benzodiazepine abuse exposure calls, 2009-2017
N%

Total Single-Substance Abuse Exposure Calls

15,779100%

People with Related Clinical Effects with
Moderate-to-Severe Medical Outcomes

2,394

100%

Moderate

2,223

92.9%

Major

162

6.8%

Death

4

0.2%

Death, indirect report

5

0.2%

Table 3.7 displays the top 25 most frequently reported clinical effect deemed by poison
center specialists to be related to the single-substance benzodiazepine exposuresdescribed above with moderate-to-severe medical outcomes. The most commonly
reported related clinical effects and corresponding frequency in these exposures included
drowsiness/lethargy (76%), slurred speech (24%), confusion (14.1%), tachycardia(13.3%), hypotension (13.3%), and ataxia (13.1%). A full frequency table of all reported

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3.10). Of these, 12,217 (10.3%) of ED visits involving nonmedical use of
benzodiazepines involved prescription opioids as the only other substance. [20] Patients
15-34 years old made up over half of the visits involving nonmedical use of
benzodiazepines and had thehighest population rate (7.4 per 10,000 persons). [20] (Appendix C Table C1).
Table 3.10. Emergency Department Visits Due to Adverse Events Involving Nonmedical Use of Benzodiazepines, by Concurrent Substance, 2016-2017a
Nonmedical Use of
Benzodiazepines
Annual Estimate

Concurrent SubstanceNo.
%
95% CI
Benzodiazepines onlyb
20,52317.2(14.6-19.9)
Benzodiazepines & one other class of substance
56,83947.7(45.3-50.3)
Illicit drugs onlyc
24,07820.2(17.3-23.1)
Alcohol only
14,096
11.8(9.2-14.4)
Prescription opioids only
12,21710.3(7.6-13.0)
Non-opioid medications only
6,448
5.4
(4.1-6.7)
Benzodiazepines & multiple classes of substances 41,646
35.0(31.2-38.8)
Non-opioid medication(s) & (illicit drugs or
17,295
14.5(12.3-16.8)
alcohol)
Prescription opioid(s) & (illicit drugs or alcohol)
9,358
7.9
(5.6-10.1)
Prescription opioid(s) & Non-opioid
8,027
6.7
(5.3-8.2)
medication(s)&/or (illicit drugs or alcohol)
Illicit drugs & alcohol
6,966
5.9
(4.6-7.2)
Total
119,008 100.0-aData are from the National Electronic Injury Surveillance System-Cooperative
Adverse Drug Event Surveillance project, CDC. Estimates based on <20 cases or total
estimates <1,200 are considered statistically unstable and are not shown (--).
b
Without documentation of involvement of other substances. Two different
benzodiazepines were involved in 8 cases involving therapeutic use, 16 cases
involving self-harm, and 24 cases involving nonmedical use.
c
Includes unspecified opioids and unspecified amphetamines. Does not include
prescription opioids, alcohol, or non-opioid medications.
Source: Moro RN, Geller AI, Weidle NJ, et al. Emergency Department Visits Involving Benzodiazepines,
United States, 2016-2017 (In Press).

The adverse clinical outcomes that were most frequently documented in ED visits
involving nonmedical use of benzodiazepines were altered mental status (44.3%) andcardiorespiratory arrest / unresponsiveness (24.2%) (Appendix C Table C2). [20]However, the frequency of cardiorespiratory arrest / unresponsiveness depended onwhether benzodiazepines were co-implicated with other substances: it was noted in
18.5% (95% CI:8.5%-28.5%) of ED visits involving benzodiazepines alone, 29.2% (95%
CI:22.2%-36.3%) of ED visits involving benzodiazepines and prescription opioids alone,and 38.0% (95% CI:28.4%-47.5%) of ED visits involving benzodiazepines and illicit
drugs alone. [18]To put the benzodiazepine ED visit data into context, in 2016, an estimated 167,845 ED
visits involved nonmedical use of benzodiazepines, compared to an estimated 129,863

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visits that involved nonmedical use of prescription opioids and substantially fewer visits
involving nonmedical use of other psychoactive prescription drugs (Table 3.11).
However, there were fewer ED visits involving nonmedical use of benzodiazepines alonecompared to ED visits involving nonmedical use of prescription opioids alone (respective
estimates, 23,335 and 40,499; Table 3.11). Also, among observed cases of ED visits
involving nonmedical use of benzodiazepines, 26.4% (95% CI:19.7%-33.1%) wereidentified by laboratory test results only. Also, in 7.4% (95% CI: 4.1%, 10.7%) of visits
involving opioids, the prescription opioid was identified by laboratory testing only.
TABLE 3.11. Emergency Department visits due to non-medical use ofpharmaceuticals, by categorya: NEISS-CADES, U.S., 2016
Implicated alone or with othersubstances,b annual national estimatedN% total visits (95% CI)

Implicated alone without other substances,c annual
national estimateeN% total visits(95% CI)
6.5 (5.1-7.9)% category (95% CI)

Benzodiazepine 167,845
46.9 (42.5-51.2)
23,33513.9 (10.9-16.9)
Prescription
129,863
36.2 (30.8-41.7)
40,499 11.3 (8.6-14.0)
31.2 (26.2-36.1)
opioids
Hypnotics (non16,899
4.7 (3.8-5.7)
2,374
0.7 (0.4-1.0)
14.1 (7.8-20.3)
benzodiazepine)
Antipsychotics
15,8744.4 (3.4- 5.5)
4,995
1.4 (1.0-1.8)
31.5 (25.6-37.3)
Muscle14,7314.1 (3.2-5.0)
3,114
0.9 (0.5-1.2)
21.1 (13.4-28.9)
relaxants
Stimulants
10,9993.1 (1.8- 4.4)
33.4 (22.1-44.8)
3,677f 1.0 (0.4-1.7)
aEstimates are from the National Electronic Injury Surveillance System−Cooperative Adverse Drug
Event Surveillance project, Centers for Disease Control and Prevention.
bImplicated alone or in combination with other pharmaceuticals, alcohol, unspeciﬁed drugs, or illicit
substances.
cImplicated alone, without other categories of pharmaceuticals, and without alcohol, unspeciﬁed drugs, orillicit substances.
dAnnual estimates and percentages total more than 100% because a single visit may involve multiple
pharmaceuticals from different categories.
eAnnual estimates and percentages total less than 100% because additional visits involve pharmaceuticals
from different categories and additional visits involve alcohol or illicit substances.
fCoefﬁcient of variation >30%.
Source: Geller AL, Dowell D, Lovegrove MC, et al. U.S. Emergency Department Visits Resulting From
Nonmedical Use of Pharmaceuticals, 2016. Am J Prev Med. 2019 May;56(5):639-647

TREATMENT EPISODE DATA SET-ADMISSIONSTEDS included data on the primary, secondary, and tertiary drugs of abuse, as reported in
830,822, 440,134, and 185,082 admissions to publicly-funded substance use disorder
treatment programs, respectively. Benzodiazepines represented 1.2% of all primary drugs
reported, 7.3% of secondary drugs, and 9.8% of tertiary drugs (Table 3.12). Alprazolam
was, by far, the most commonly reported benzodiazepine abused. For context, opioid
analgesics were 3.1% of all primary drugs, 2.9% of secondary drugs, and 2.4% of tertiarydrugs. Non-pharmaceutical substances—including alcohol, heroin, marijuana/hashish,

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methamphetamine/speed, and cocaine—were reported as primary drugs of abuse in thelarge majority of admissions.

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Table 3.12. Benzodiazepines and other drugs endorsed as the primary, secondary,and tertiary drug of abuse at substance use treatment admissions: TEDS, U.S., 2017
Primary Drug of
Abuse

Secondary Drug of
Abuse

Tertiary Drug of Abuse(N=830,822)(N=440,134)(N=185,082)

N

Drug Reported

Benzodiazepines total

Percent of N
Admissions
withPrimary
Drug
Reported

10,316

1.2

Percent of N
Admissions
withSecondary
Drug
Reported
32,415

7.3

Percent of
Admissions
withTertiary
Drug
Reported
18,166

9.8

Alprazolam
6,152
0.7
18,990
4.3
10,093
Clonazepam
248
*
860
0.2
444
Diazepam
575
0.1
2,362
0.5
1,348
Lorazepam
69
*
196
*
112
Other benzodiazepines
3,272
0.4
10,007
2.3
6,169
Opioid analgesics total**
26,2973.1
12,653
2.9
4,429
Drugs most frequently
reported as primary drugof abuse
Alcohol
274,32133.0
75,43617.1
32,221
Heroin255,76230.8
30,266
6.9
8,241
Marijuana/hashish
97,421
11.7 106,169
24.1
50,830Methamphetamine/speed 51,952
6.3
25,463
5.8
8,628
Cocaine48,043
5.8 109,497
24.9
35,358* Less than 0.05 percent** TEDS collected data on the following opioid analgesics: codeine, hydrocodone,hydromorphone, meperidine, oxycodone, pentazocine, propoxyphene, and tramadol. This total
did not include opioids for treating addiction, e.g., buprenorphine and methadone.
Source: Treatment Episode Data Set (TEDS) 2017, Table 2.18. Center for Behavioral Health
Statistics and Quality, Substance Abuse and Mental Health Services Administration.

5.5
0.2
0.7
0.1
3.3
2.4

NATIONAL VITAL STATISTICS SYSTEM-MORTALITY
For the period from 2013 to 2017, the most recent five years of available data from the
NVSS-M, there were 45,930 benzodiazepine-involved drug poisoning (overdose) deaths(Table 3.13). Among these deaths, 55.3% (n=25,421) involved prescription opioids withor without other drug substances, and 8.4% (n=3,837) involved psychostimulants withabuse potential with or without other drug substances. Among the deaths involving bothbenzodiazepine and prescription opioids, only 17.5% (n=4,454) had no documentation ofanother involved drug substance (drug substance: T36.0 to T50.9; does not include
alcohol (T51.0)).
Among all benzodiazepine-involved poisoning deaths, only 3.2% (n=1,448) involved
benzodiazepines with no indication of involvement of another drug (drugs identified by
T36.0 to T50.9; these codes do not include alcohol (T51.0)), and 2.0% (n=928) were due

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17.4
4.5
27.5
4.7
19.1

to benzodiazepines alone, with no code indicating another drug or alcohol (Table 3.13).
Almost 20% (19.82%; n=287) of these single-drug deaths were intentional, nearly double
the percentage of intentional deaths among all benzodiazepine-involved deaths (11.5%;
n=5297). Also, among these single-drug benzodiazepine deaths, approximately 35.9%(n=520) involved alcohol, approximately three times the percent of deaths involving
alcohol among all benzodiazepine-involved deaths (12.3%; n=5648).
Table 3.13. Number (%) of deaths involving benzodiazepines, by decedent characteristics and other drug
substances involved, U.S. Residents, 2013-2017, where underlying cause of death is drug poisoninga,
NVSS-M

Benzodiazepine

Benzodiazepine
as single drug
substance b

N (% of row)

Benzodiazepine
and prescription
opioids

Benzodiazepine
and prescription
opioids only

Benzodiazepine andpsychostimulants ofabuse potential

N (% of row)

N (% of row)

N (% of row)

N (% of row)

45930 (100.00)

1448 (3.15)

25421 (55.35)4454 (9.70)

3837 (8.35)

N (% of column)

N (% ofcolumn)N (% of column)

N (% of column)

N (% of column)

Female19423 (42.29)

556 (38.40)

11535 (45.38)

1669 (37.47)

1467 (38.23)

Male26507 (57.71)

892 (61.60)

13886 (54.62)

2785 (62.53)

2370 (61.77)

Total
Sex

Age Group (years)<10

16 (0.03)

1 (0.07)8 (0.03)3 (0.07)1 (0.03)10-19

720 (1.57)

18 (1.24)

344 (1.35)

96 (2.16)

57 (1.49)

20-39

19091 (41.57)

423 (29.21)

9347 (36.77)

1721 (38.64)

2177 (56.74)

40-59

21282 (46.34)

718 (49.59)

12869 (50.62)2172 (48.77)

1417 (36.93)

60-642798 (6.09)

128 (8.84)

1734 (6.82)

276 (6.20)

136 (3.54)

65+

2020 (4.40)

159 (10.98)1118 (4.40)

185 (4.15)

49 (1.28)

3 (0.01)1 (0.07)1 (0.00)

1 (0.02)--

Yes

38545 (83.92)

1048 (72.38)

21693 (85.33)

3925 (88.12)

3441 (89.68)

No7385 (16.08)

400 (27.62)

3728 (14.67)

529 (11.88)

396 (10.32)

Yes5297 (11.53)

287 (19.82)

2509 (9.87)

291 (6.53)

239 (6.23)

No40633 (88.47)

1161 (80.18)

22912 (90.13)4163 (93.47)

3598 (93.77)

Missing
Unintentional

Intentional

Assault/ Homicide
Yes

43 (0.09)

4 (0.28)

17 (0.07)

4 (0.09)10 (0.26)

No45887 (99.91)

1444 (99.72)

25404 (99.93)

4450 (99.91)

3827 (99.74)

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users [33]. One study found that persons living as single, separated, divorced or widowed
had a higher likelihood of long-term benzodiazepine use [32], and the second study
identified living alone as a protective factor [33] for chronic benzodiazepine use.
Although similar concepts, these studies likely assessed different constructs of living
alone, such as marital status versus independent living. These studies differed in that one
study excluded patients with chronic benzodiazepine use at baseline [33] and the other
did not, eliminating its ability to assess temporality [32]. Further, their definitions oflong-term or chronic use were different.
A longitudinal study of U.S. veterans with posttraumatic stress disorder (PTSD)
examined risk factors for receiving high dose benzodiazepines, defined as dosage in the
top 10% of average daily doses, among patients with at least three prescription fills
within a 120-day period [30]. This study included patients with new prescriptions for any
of four anxiolytic benzodiazepines (alprazolam, clonazepam, diazepam, and lorazepam),and used longitudinal data from pharmacy and administrative claims databases to follow
patients over a 6-year observation period. The study found that having a drug abuse
diagnosis increased the risk of subsequent high-dose benzodiazepine use among thosewith long-term use. Using multivariable logistic regression, the study found that among
PTSD patients with an alcoholism diagnosis, multiple factors resulted in increased odds
of being prescribed a high dose of benzodiazepines. These factors were: younger age,having a drug abuse diagnosis, multiple concurrent benzodiazepine prescriptions, andconcurrent acetaminophen/oxycodone prescriptions [30].
Two cross-sectional studies found that benzodiazepine dose and duration were positively
associated with benzodiazepine dependence, but the study designs precluded a
determination of the extent to which dose and duration contributed to benzodiazepine
dependence [34] [31]. One study, which enrolled 1,048 consecutive patients who hadtaken benzodiazepines daily for at least one month and who were attending primary
healthcare centers in Spain, found that benzodiazepine dependence, as measured by aself-report questionnaire (severity of dependence scale), was more common among
women, and middle aged persons, and 47% of patients using benzodiazepines for morethan 1 month reported dependence [34]. The second study described patients (n=401)
who were currently using benzodiazepines and enrolled into a study of depression andanxiety from general practice and mental health care institutions in the Netherlands. The
study assessed the cross-sectional association between patient score on a questionnaire tomeasure benzodiazepine dependence, the Bendep-SRQ, and various socio-demographic,
psychological, physical, substance-use, and benzodiazepine-use related factors [31]. In
multivariable-adjusted models, insomnia, antidepressant use, and alcohol dependence
were associated with higher scores for benzodiazepine dependence. Similarly, bothstudies found benzodiazepine dependence was positively associated with antidepressantuse (in one study this was true only before multivariable adjustment), but it was
impossible to determine temporality, or to distinguish antidepressant use from depressivemood.
Finally, one study reported on characteristics of general practice patients with current orformer long-term benzodiazepine use in the Netherlands and factors associated withbenzodiazepine cravings [35]. Patients (n=193) completed questionnaires assessing
benzodiazepine cravings, dependence severity, mood state, personality and lifestyle

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characteristics. Craving was reported by 22.5% of the patients who had discontinued theiruse vs 40.7% of those who had not. Benzodiazepine dependence, psychopathology,
negative mood state, and personality were associated with the patient reporting cravings.
However, several limitations should be noted, including a low response rate (67%); andthe potential for recall bias, especially considering the patients with former long-term
benzodiazepine use [35].
In summary, studies found that female sex was positively associated with longterm/chronic use and dependence [32] [34] [33]. Other demographic factors associatedwith dependence, long-term, or high-dose benzodiazepine use included low educationand low income [34] [32]. Multiple studies found older age to be associated with longterm/chronic use or high-dose benzodiazepine use [32] [30] [33]. Depression andconcomitant antidepressant use were found to be associated with dependence, cravingsand chronic/ long-term use [32] [31] [35] [33]. Other comorbid conditions associatedwith dependence or long-term benzodiazepine use included alcohol dependence andmental health conditions generally [31] [30].
Social factors influencing misuse and abuse of benzodiazepine drugs
At an inpatient drug treatment program in Texas in 2004, researchers interviewed 46
patients from ages 12 to 21 years old who reported they currently used alprazolam [36].
Current use was defined as at least once in the past 30 days. Participants were asked ten
open-ended questions, including “why do you think Xanax is so popular?” Euphoric
effect, price, self-medication and peer pressure were reported as answers to this question.
High social approval was also mentioned as a reason that participants felt teenagers use
Xanax, and the themes of high social approval and peer pressure were common
throughout the interviews. This study provided insight into perceptions about alprazolam
misuse and abuse; however, the study did not inquire about preference for alprazolam
over other benzodiazepines.
The second study interviewed 13 young adults, ages 18 to 21 years, who abusedbenzodiazepines currently or in the past and who were receiving substance use services inCork, Ireland from 2012-2013. [37]. Interview questions and study results did not
differentiate between different benzodiazepines and instead reported on benzodiazepines
generally, reporting motivations for and consequences of benzodiazepine abuse.
Motivations included, to feel stoned or other similar terms to suggest relaxation, and to
avoid daily stressors. The responses in this study focused more on the effects ofbenzodiazepine misuse, such as effects on family life, negatives of benzodiazepine
misuse, and effects on social functioning. A minority of the responses were focused on
the perceived benefits of benzodiazepine misuse, including being stoned, increased selfconfidence and dissociation. There was little focus on peer pressure or social influence ona desire to misuse benzodiazepine. However, interviews were semi-structured, andcommon themes and responses elicited may have been influenced by the interviewer’s
adaptation of the interview guide.
Both studies were conducted among young adults and reported similar findings of theparticipants’ desire to get high and escape daily problems. However, only the study from
Texas [36] reported on external, social influences for the use of a specificbenzodiazepine, perhaps due to the questions asked of the participants. Neither article

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provided insight into potential preference for a specific benzodiazepine product overanother.
FAERS
High-Level Overview of FAERS Reports
Please note that these results may include duplicate reports for the same patientfrom multiple reporters (e.g., manufacturer, family member, physician, pharmacist,
nurse, etc.); causality and the role of the product in the coded event of drug abuse,dependence, and withdrawal have not been determined for the reports in thissection.
We used the FAERS search strategy described in Table 2.7 and retrieved 58,921 reports,of which 15,038 reports are also accounted for in NPDS.
Figure 3.15 shows all reports distributed by initial FDA received year with two
trendlines; one showing all reports and the second showing all reports excluding thosealso reported to NPDS. There are two noticeable spikes in the all reports in FAERS
trendline, one in 2014 and another in 2018. It should be noted that benzodiazepines havereceived increased media attention over the past several years, which may haveinfluenced reporting of AEs to FAERS involving benzodiazepines. In addition, thenumber of total FAERS reports received by the FDA has steadily increased in recent
years, with a large increase from 1,815,346 reports in 2017 to 2,155,067 reports in 2018.
[38] The date range for our FAERS search ended midway through 2019, creating theappearance of a spike in reporting in 2018. The increase in overall reporting to FAERS
combined with the partial 2019 data shown in Figure 3.16 may explain the appearance ofan increase in reports in 2018.

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Figure 3.16 displays the total report counts by suspect product active ingredient for the
top eight most frequently reported benzodiazepines in FAERS with respect to the Drugabuse dependence and withdrawal (SMQ) Broad search. The four most frequently
reported benzodiazepines were alprazolam, diazepam, lorazepam, and clonazepam, listed
in decreasing order of frequency.
Figure 3.16. FAERS Reports by Suspect Product Active Ingredient through June 30,
2019 for the Most Frequently Reported Benzodiazepines and Drug abusedependence and withdrawal (SMQ) Broad Search, Excluding NPDS (N=43,883*)
Number of FAERS Reports

16,00014,00012,00010,0008,000

13,660
10,200
8,915
6,610

6,000
4,000

2,538

2,110

2,000

1,810

1,523

0

Suspect Product Active Ingredientes*May include duplicate reports for the same patient from multiple reporters (e.g., manufacturer, family
member, physician, pharmacist, nurse, etc.); we have not assessed the causality and the role ofbenzodiazepines in the coded event(s).
FAERS = FDA Adverse Event Reporting System; NPDS = National Poison Data System; SMQ =Standardised MedDRA Query73
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Table 3.14. Descriptive Characteristics of FAERS Reports of Benzodiazepines andDrug abuse dependence and withdrawal (SMQ) Broad Search, and FAERS Reports
With Concomitant Opioid(s)*, Excluding NPDS, Received by FDA through June 30,
2019
All Reports
With Concomitant†
N=43,883
Opioid(s)†N=10,426
Type of Report
Expedited (15-day)
35,1198,674
Non-expedited
7,126
1,622
Direct1638
130
Initial FDA
1968 – 1975304
10Received Year1976 – 1985
1,012
25
1986 – 1995
5,771
124
1996 – 2005
5,137
1,782
2006 – 2015
15,533
4,342
2016 – 201916,126
4,143Country Derived
United States
17,590
5,364
Italy
6,577
226
France4,545
1,056Great Britain
4,146
1,142
Germany
1,915
321
Austria
1,192
641
Canada
1,148
613
Japan
1,141
31
Sweden749
231
Brazil
648
2
Other
4,232
799
Outcome§Death
10,4486,302
Life-threatening
3,634
722
Hospitalization
19,123
2,497
Disability
2,056
91
Other serious
19,9384,201
Non-serious
2,819
145
*

The following product active ingredients and product names were considered opioids for the purpose ofthis review and used to filter for reports with concomitant opioid(s): “buprenorphine,” “carfentanil,”“codeine,” “fentanyl,” “hydrocodone,” “hydromorphone,” “methadone,” “morphine,” “oxycodone,”“oxymorphone,” “Demerol,” “Dilaudid,” “Duragesic,” “Kadian,” “Opana,” “Oxycontin,” “Percocet,”“Roxicodone,” “Subutex,” and “Vicodin”†
May include duplicate reports for the same patient from multiple reporters (e.g., manufacturer, family
member, physician, pharmacist, nurse, etc.); we have not assessed the causality and the role ofbenzodiazepines in the coded event(s).
‡Ages expressed as negative numbers in FAERS reports (in utero exposures) were not included in the age
calculations§
For the purposes of this review, the following outcomes qualify as serious: death, life-threatening,
hospitalization (initial or prolonged), disability, congenital anomaly, required intervention and otherserious important medical events. A case may have more than one serious outcome.
FAERS = FDA Adverse Event Reporting System, NPDS = National Poison Data System, SMQ =Standardised MedDRA Query76
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3.9.1.1 Analysis of Fatal Reports Identified in FAERS High-Level Overview
Notably, 60% of fatal reports of benzodiazepines and abuse, dependence, or withdrawal,
reported concomitant opioid(s). Approximately 3% (n=343) of the 10,448 fatal reports ofabuse, dependence, or withdrawal involved only a benzodiazepine (i.e., single drug
substance, without coded concomitant substances or illicit substances mentioned in the
narrative). We did not conduct a report-level review of these reports; therefore, there
may be reports that involve other unknown substances not coded in the report or captured
in our narrative text search. It is important to note that causality has not beenassessed for this high-level overview; therefore, conclusions cannot be drawn
regarding the role of benzodiazepines and their contribution to the fatal outcome.
Table 3.17 provides the product active ingredients reported in the 343 benzodiazepine
single drug substance fatal reports.
Table 3.17. Frequency of Product Active Ingredients Reported in Fatal* FAERS
Reports of Abuse, Dependence, or Withdrawal with a Benzodiazepine as a Single
Drug Substance† through June 30, 2019, Excluding NPDS (N=343)
Product Active Ingredients‡

Number of Reports§ (%)

Triazolam

141 (41.1)

Alprazolam

69 (20.1)

Diazepam56 (16.3)

Clonazepam

35 (10.2)

Temazepam

15 (4.4)

Lorazepam

14 (4.1)

Midazolam hydrochloride

8 (2.3)Estazolam

3 (0.9)Oxazepam

2 (0.6)*Causality has not been assessed for this high-level overview; therefore, conclusions cannot be drawn
regarding the relatedness of these adverse events to benzodiazepines or the role of benzodiazepines
and their contribution to the fatal outcome.
†We removed those reports that had any concomitant medications coded. We then used a narrative text
search for the following terms to further identify and remove cases of multiple drug exposures and thosewith illicit substances mentioned in the narrative only: “multiple drug overdose,” “THC,” “marijuana,”“cocaine,” “opiate,” “alcohol,” “heroin.” We did not conduct a report-level review of these reports;
therefore, there may be reports that involve other unknown substances not coded in the report or captured in
our narrative text search.
‡
A report may have more than one product active ingredient.
§
May include duplicate reports for the same patient from multiple reporters (e.g., manufacturer, family
member, physician, pharmacist, nurse, etc.).
FAERS = FDA Adverse Event Reporting System; NPDS = National Poison Data System

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Upon screening the 141 triazolam fatal reports, only 44% (n=62) actually reported
triazolam as a single drug substance. Of those 62 reports, approximately 50% were deathby suicide or possible overdose, and 25% were accidental deaths (e.g., house fire afteringestion of triazolam), homicides, or deaths of an unconfirmed cause. The remaining
25% were unrelated to triazolam or lacked information necessary to fully evaluatecausality (e.g., time of ingestion of drug relative to AE, dose, concomitant medications,medical history of the patient).

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Table 3.18 provides a breakdown of PTs in the 343 benzodiazepine single drug substancefatal reports.
Table 3.18. Frequency of Top 15 PTs Reported in Fatal* FAERS Reports ofAbuse, Dependence, or Withdrawal with a Benzodiazepine as a Single Drug
Agent† through June 30, 2019, Excluding NPDS (N=343)
PTs*

Number of Reports‡ (%)

Overdose

180 (52.5)

Intentional overdose

69 (20.1)

Death

57 (16.6)

Suicide attempt

28 (8.2)

Completed suicide

26 (7.6)

Drug dependence

22 (6.4)

Drug withdrawal syndrome

17 (5)Coma

16 (4.7)

Accidental overdose

13 (3.8)

Cardiac arrest

12 (3.5)

Drug level above therapeutic

12 (3.5)

Intentional product misuse

10 (2.9)

Withdrawal syndrome

9 (2.6)

Drug abuse

8 (2.3)

Seizure8 (2.3)*Causality has not been assessed for this high-level overview; therefore, conclusions cannot be
drawn regarding the relatedness of these adverse events to benzodiazepines or the role ofbenzodiazepines and their contribution to the fatal outcome. A report may have more than one
coded PT.
†We removed those reports that had any concomitant medications coded. We then used a narrative text
search for the following terms to further identify and remove cases of multiple drug exposures and thosewith illicit substances mentioned in the narrative only: “multiple drug overdose,” “THC,” “marijuana,”“cocaine,” “opiate,” “alcohol,” “heroin.” We did not conduct a report-level review of these reports;
therefore, there may be reports that involve other unknown substances not coded in the report orcaptured in our narrative text search.
‡
May include duplicate reports for the same patient from multiple reporters (e.g., manufacturer, family
member, physician, pharmacist, nurse, etc.)
FAERS = FDA Adverse Event Reporting System; NPDS = National Poison Data System; SMQ =Standardised MedDRA Query; PT = Preferred Term

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Tables 3.19 and 3.20 describe the remaining 3,803 fatal reports of benzodiazepines withconcomitant drugs other than opioids. Table 3.19 includes the product active ingredients
other than benzodiazepines that were coded in these reports, but their relative
contribution to the fatal outcome has not been assessed at the report level. Table 3.20
provides a breakdown of PTs reported in these reports.
Table 3.19. Frequency of All Product Active Ingredients Reported with
Benzodiazepines in Fatal* FAERS Reports of Abuse, Dependence, or Withdrawal
through June 30, 2019, Excluding Concomitant Opioid(s) and NPDS (N=3,803†)
Product Active Ingredients†

Number of Reports‡ (%)

Alcohol

404 (10.6)

Citalopram hydrobromide

276 (7.3)

Acetaminophen

259 (6.8)

Fluoxetine hydrochloride

243 (6.4)

Zolpidem tartrate214 (5.6)

Quetiapine

207 (5.4)

Olanzapine

201 (5.3)

Venlafaxine

177 (4.7)

Mirtazapine

164 (4.3)

Pregabalin

164 (4.3)

Tramadol156 (4.1)

Sertraline

154 (4)*Causality has not been assessed for this high-level overview; therefore, conclusions cannot be
drawn regarding the relatedness of these adverse events to benzodiazepines or concomitant drugs
or the role of benzodiazepines or concomitant drugs and their contribution to the fatal outcome.
†A report may have more than one product active ingredient‡
May include duplicate reports for the same patient from multiple reporters (e.g., manufacturer, family
member, physician, pharmacist, nurse, etc.)
FAERS = FDA Adverse Event Reporting System; NPDS = National Poison Data System

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Table 3.20. Frequency of Top 15 PTs Involved in Fatal* FAERS Reports ofAbuse, Dependence, or Withdrawal with Benzodiazepines through June 30, 2019,
Excluding Cases with Concomitant Opioid(s) and NPDS (N=3,803)
Number of Reports† (%)

PTs
Toxicity to various agents

1,662 (43.7)

Overdose

1,118 (29.4)

Intentional overdose

732 (19.2)

Completed suicide714 (18.8)

Accidental overdose

333 (8.8)

Drug interaction

314 (8.3)

Drug abuse

249 (6.5)

Suicide attempt

235 (6.2)

Coma

234 (6.2)

Cardiac arrest

221 (5.8)

Death

212 (5.6)

Pulmonary oedema

172 (4.5)

Hypotension

153 (4)

Respiratory depression

141 (3.7)

Depressed level of consciousness

140 (3.7)*Causality has not been assessed for this high-level overview; therefore, conclusions cannot be
drawn regarding the relatedness of these adverse events to benzodiazepines or the role ofbenzodiazepines and their contribution to the fatal outcome. A report may have more than one
coded PT.
†
May include duplicate reports for the same patient from multiple reporters (e.g., manufacturer, family
member, physician, pharmacist, nurse, etc.)
FAERS = FDA Adverse Event Reporting System; NPDS = Nation Poison Data System; PT = Preferred
Term

FAERS Case Selection for Report-Level Review
We used the FAERS search described in Table 2.7 and retrieved 346 reports. After
applying the case definition in Section 2.10.3 and accounting for duplicate reports, we
included 104 cases in our case series of abuse, dependence, or withdrawal reported withbenzodiazepine as a single drug substance (i.e., monotherapy) (see Figure 3.19).

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Table 3.21. Descriptive Characteristics of Abuse, Dependence, or Withdrawal
with Benzodiazepine as a Single Drug Substance Direct Reports to FDA,
Received by FDA through June 30, 2019 (N=104)
Reporter
Patient
82
Prescriber
13
Pharmacist
5
Patient’s relative
4†*
Reason for Use, n=102
Anxiety59
Depression
6
Insomnia
22
Panic attack or panic disorder17
Post-traumatic stress disorder
4
Other‡
8§
Original Source of Drug
Prescription
102
Unknown2
Initial FDA Received Year1968 – 1975
31976 – 1985
3
1986 – 1995
13
1996 – 2005
32
2006 – 2015
392016 – 201914
Type of Event*ǁ
Abuse
4
Dependence
90
Withdrawal
94¶
OutcomeLife Threatening
21
Hospitalization
29
Disability
33
Other serious
53
Required intervention
17
Non-serious
12*A case may report more than one.
†
Anxiety includes any of the following reasons for use: acute anxiety, anxiety, nerves, pre-procedureanxiety, social anxiety disorder, situational anxiety‡
Other reasons for use included: alcoholism (n=1), Bipolar, mixed (n=1), cerebellar syndrome (n=1),
chronic nausea (n=1), drug abuse (n=1), neuromuscular pain (n=1), obsessive compulsive disorder(n=1), vertigo (n=1).
§
Zero cases reported obtaining the benzodiazepine by illegal means.
ǁAbuse, dependence and withdrawal determination made by using definitions in Tables 2.5 and 2.6 in
Section 2.10.1 after report-level review of the case narrative, rather than using MedDRA coded
events.
¶For the purposes of this review, the following outcomes qualify as serious: death, life-threatening,
hospitalization (initial or prolonged), disability, congenital anomaly, required intervention and otherserious important medical events. A case may have more than one serious outcome.
FAERS = FDA Adverse Event Reporting System; MedDRA = Medical Dictionary for Regulatory
Activities

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All but two cases in this case series described AEs that developed with prescription useof benzodiazepines. There were no cases that either described obtaining benzodiazepines
by illegal means or that described patients who started out with a valid prescription for abenzodiazepine and then switched to obtaining the drug by illegal means. Four of the
104 cases included in this case series described a case of benzodiazepine abuse. It is
important to note that there may be a bias against identifying cases of abuse or illicit use
because we limited our search to direct reports only. We assume that patients generally
do not self-report abuse or illicit use of substances to the FDA, and most cases in thiscase series (n=82, 79%) were submitted by the patients themselves.
Table 3.22 below displays the median and range of the following data points from thiscase series: time to onset of symptoms of dependence or tolerance, duration of
benzodiazepine use, and duration of withdrawal symptoms. Because of the spontaneous
nature of the reports, incidence of a given AE cannot be calculated using FAERS
data and comparisons between drugs are not accurate.
Table 3.22. Time to Onset of Dependence, Duration of Use, and Duration ofWithdrawal Symptoms* in Direct Reports to FDA of Abuse, Dependence, orWithdrawal for Benzodiazepines as a Single Drug Substance, Received by FDA
through June 30, 2019

All Reported
Benzodiazepines
Alprazolam

Clonazepam

DiazepamLorazepam

TriazolamOxazepamMedian (Range)
Time to Onset of
Dependence orTolerance, days
14
(1 day to 4 years)
N=45
3(1 day to 1 year)
N=13
20.5
(1 day to 3 years)
N=18
3
N=1
21 (1 day to 4
years)
N=12
21
N=1
---

Median (Range)
Duration of Use, months

19.5(6 days to 25 years)
N=96
18(6 days to 10 years)
N=2730(1 month to 25 years)
N=41
12(3 months to 2.5 years)
N=3
10(21 days to 18 years)
N=21
10 (2 months to 3 years)
N=3
24
N=1

Median (Range)
Duration ofWithdrawal
Symptoms, months
9.5(2 weeks to 8 years)
N=44
21(12 weeks to 5 years)
N=8
13(2 weeks to 5 years)
N=25
26
N=1
3.5
(2 weeks to 8 years)
N=92 weeks
N=1---*Incidence of a given adverse event cannot be calculated using FAERS data and comparisons between
drugs are not accurate.
FAERS = FDA Adverse Event Reporting System

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Notably, 18 of the 44 cases that provided duration of withdrawal information also statedthat withdrawal symptoms were still ongoing at the time of the report. The breakdown by
product for the cases describing ongoing withdrawal is as follows: lorazepam (n=6),
alprazolam (n=5), clonazepam (n=5), diazepam (n=1), triazolam (n=1).
Approximately 80% (83/104) of the cases in this case series described specific symptoms
of withdrawal. Table 3.23 on the following page provides a summary of the top 20
verbatim (not coded MedDRA term) symptoms of withdrawal reported in this case series.
We included the number and percentage of cases in which each symptom was reported
for all benzodiazepines, and the number of cases for each of the top four reported
benzodiazepines (alprazolam, diazepam, lorazepam, and clonazepam).

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Table 3.23. Symptoms of Withdrawal Described in >5% of Direct Reports to FDA of Abuse, Dependence or Withdrawal
with Benzodiazepine as a Single Drug Substance, Received by FDA through June 30, 2019 (N=83)
Verbatim terms*

All Reported
Benzodiazepines

Alprazolam

Clonazepam

DiazepamLorazepam

N=23

N=35

N=3

N=19

N=83†(%)
Insomnia

32 (38.6)

11

13

1

6

Anxiety or panic

27 (32.5)

6

11

0

9

Heart palpitations; Tachycardia or bradycardia;
Non-specific arrhythmias

24 (28.9)

8

8

1

6

Gastrointestinal (GI) upset (includes nausea,
diarrhea, or other non-specific GI symptoms)

23 (27.7)

6

12

0

3

Headache or migraine (includes head pressure, headpain)

18 (21.7)

2

12

0

4

Dizziness, lightheadedness, or vertigo

18 (21.7)

6

7

0

4

Memory impairment, confusion, disorientation,
cognitive decline, cognition issues, or dementia

17 (20.5)

2

10

0

4

Pain

16 (19.2)

4

8

0

3

Depression

13 (15.7)

4

6

1

2

Tremor(s) or trembling

13 (15.7)

3

7

0

2

Sweating or diaphoresis

13 (15.7)

4

4

0

4

Suicidal ideation or suicide attempt

12 (14.5)

1

9

0

2

Hypertension

9 (10.8)

4

2

1

2

Derealization or depersonalization

9 (10.8)

2

3

0

4

Convulsions, myoclonus, shakes or twitching

9 (10.8)

1

4

2

2

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Table 3.23. Symptoms of Withdrawal Described in >5% of Direct Reports to FDA of Abuse, Dependence or Withdrawal
with Benzodiazepine as a Single Drug Substance, Received by FDA through June 30, 2019 (N=83)
Verbatim terms*

All Reported
Benzodiazepines

Alprazolam

Clonazepam

DiazepamLorazepam

N=23

N=35

N=3

N=19

N=83†(%)
Muscle spasms, cramps, or "locked muscles"(includes involuntary muscle contractions)

8 (9.6)

1

7

0

0

Fatigue

7 (8.4)

3

1

0

3

Weight loss or weight increase

6 (7.2)

0

2

0

3

Withdrawal seizure

5 (6)

4

0

1

0

Hallucinations (auditory or visual); delirium

5 (6)

3

2

0

0

Vivid dreams (including nightmares)

5 (6)

1

4

0

0

Brain zaps, head jolts, electric shocks

5 (6)

1

4

0

0

Loss of appetite

5 (6)

1

2

0

2

Rage, agitation

5 (6)

1

2

0

1

Agoraphobia, fear

5 (6)

0

2

0

3

*These verbatim terms were extracted directly from the case narratives. We grouped similar terms together and manually tallied the results. Most cases reported more than one
symptom of withdrawal. Verbatim terms that were described less than 5% of cases, listed in descending order, include: akathisia (including restlessness); tinnitus or hearing
disturbance; paraesthesias or extremity numbness; photosensitivity or visual disturbances; breathing or non-specific respiratory problems; paranoia; difficult concentrating; flulike symptoms; mood swings or mood lability; dilated pupils; slurred speech. Incidence of a given adverse event cannot be calculated using FAERS data andcomparisons between drugs are not accurate.
†

Two cases with oxazepam and one case with triazolam described specific symptoms
FAERS = FDA Adverse Event Reporting System

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Thirteen out of 104 cases described the need for additional or more prominent warnings
on benzodiazepines or increased prescriber education about the potential for dependence
and subsequent withdrawal. Several cases specifically mentioned the need for a Boxed
Warning, an example of which is summarized below in Section 3.8.2.1.
3.9.2.1 Example Cases from the FAERS Case Series of Direct Reports of Drug
Abuse, Dependence and Withdrawal with Benzodiazepine as a Single Drug
Substance
Case 1
FAERS# 6167935, Version 1, Initially received by FDA October 2006
Drug of Interest: Clonazepam
Outcomes: Life threatening, Other serious
A 41-year-old male patient was prescribed clonazepam 0.5 mg every 12 hours as needed
for anxiety. He reports that he never received any re-evaluation or follow up after
receiving this initial prescription and because he was taking less than the amountprescribed, he thought “he would never have a problem with becoming physicallydependent on the drug.” He reports that the withdrawal he experienced was much worse
than the anxiety symptoms he had to begin with. After approximately six months, thepatient began to have dizziness that his doctors did not attribute to clonazepam, butinstead to the patient’s worsening anxiety. He continued with clonazepam for three moremonths at which point he decreased his dose by half and began to experience thefollowing symptoms: “dizzy, nausea, floor moving sensations, head feeling pressurized,
vibrating in skull.” A psychiatrist recommended that the patient stop the drug “coldturkey” because the patient was on a “low dose.” The patient stopped clonazepam andexperienced “complete loss of appetite, weight loss, nausea, dizziness, insomnia.” These
symptoms reportedly lasted approximately three months and at the time of the report thepatient felt “99% better” and remained off clonazepam. The patient further states that thereason he wrote his MedWatch report was “in the hopes of getting a Black Box Warningon Benzodiazepines. There is nothing in the information sent out with the drug regarding
the symptoms of dependency and the signs of interdose withdrawal, tolerance, the speedof dependency …or the fact that people can get dependent on a low dose as neededbenzo.”
Reviewer’s comment: This case describes a patient who was prescribed a “low dose”
clonazepam on an as needed basis and experienced symptoms of dependency after six
months of use followed by three months of withdrawal symptoms after stopping the drug.
Notably, he described the withdrawal symptoms as much worse than the anxiety
symptoms that the clonazepam was prescribed to manage. The initial dose for panic
disorder in the clonazepam product labeling is 0.25 mg twice daily, making his
prescribed dose twice that of the recommended dose. Additionally, he may haveexperienced less severe withdrawal symptoms or no symptoms had he been instructed totaper as the product labeling recommends: “Treatment should be discontinued
gradually, with a decrease of 0.125 mg twice daily every 3 days, until the drug iscompletely withdrawn.” Furthermore, the product labeling also includes
recommendations that “… the physician who elects to use Klonopin for extended periods

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should periodically reevaluate the long-term usefulness of the drug for the individual
patient.” This patient reported that he was not re-evaluated after receiving the initialprescription, with which he continued for six months. He feels strongly that additional
warnings are warranted on benzodiazepines. He may not have experienced the AEs if theexisting product labeling recommendations were followed for dosing, monitoring, andtapering schedule.
The following is an excerpt from the DRUG ABUSE AND DEPENDENCE section of thecurrent product labeling for clonazepam which contains the same language as theversion from August 2006:“The more severe withdrawal symptoms have usually been limited to those patients
who received excessive doses over an extended period of time. Generally milder
withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following
abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels
for several months. Consequently, after extended therapy, abrupt discontinuation
should generally be avoided and a gradual dosage tapering schedule followed (seeDOSAGE AND ADMINISTRATION). Addiction-prone individuals (such as drug
addicts or alcoholics) should be under careful surveillance when receiving
clonazepam or other psychotropic agents because of the predisposition of suchpatients to habituation and dependence.” [39] [40]This reviewer concurs that, while there are adequate warnings regarding the potential
for dependence and withdrawal in the clonazepam product labeling, information islacking regarding the potential for dependence and withdrawal at low or as needed
dosing in patients without a history of substance use disorder or dependence. This
reviewer also believes that there is a need for re-educating healthcare professionals
regarding the appropriate use of benzodiazepines, and reinforce that the instructions on
dosing, monitoring, and tapering schedule are included in the product labeling forreference.
Case 2
FAERS# 5923616, Version 1, Initially received by FDA November 2005
Drug of Interest: Clonazepam
Outcomes: Hospitalization, Life threatening, Other serious
A 34-year old female patient was prescribed clonazepam for insomnia (early morning
waking) that began after starting sertraline. The initial prescribed dose was 0.5 mg once
daily. While taking clonazepam, her “body became addicted” and she began to“experience withdrawals” while on the drug. The prescribing physician increased thedose so that “she could feel normal again.” By eight weeks, her clonazepam dose had
been increased to 2 mg daily. At this point, the patient realized that she was “completely
addicted” and began to wean her dose by ¼ tablet every one to three months. She began
to experience more withdrawal symptoms with each dose reduction including “reboundanxiety, insomnia, vertigo affecting driving, vomiting, chills, profound muscle cramping,shakes, nightmares…twitches, memory loss, agitation to extreme, limbs going numb.”
When she went to her physician about these symptoms, he told her “symptoms could not
be from withdrawal…tons of practitioners were trying to figure it out.” The patient wasreferred to a neurologist who tested her for Parkinson’s disease, multiple sclerosis, and a92
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brain tumor, and “all tests were normal.” It took the patient one year to wean off of 2 mg
because of the withdrawal symptoms. The patient said, “I have experienced this drug tobe horrendously addictive at low, normal prescribed dosages and it was extremely
dangerous to my well-being.”
Case 3
FAERS# 5923616, Version 1, Initially received by FDA April 2005
Drug of Interest: Alprazolam
Outcomes: Life threatening, Other serious
An adult female patient of unknown age was prescribed alprazolam 0.25 mg three times
daily for anxiety after an ED visit for chest pain. Within days of starting alprazolam, thepatient began experiencing what she described as “tolerance withdrawal” and begansuffering from “severe head pressure, dizziness, panic attacks and eventually a total
nervous breakdown.” The patient presented several times to her family doctor with these
symptoms and he never attributed them to alprazolam, but instead told her that sheneeded to “double up” her dose. The patient ended up having multiple tests done
including an MRI to rule out a brain tumor and multiple sclerosis, and an echocardiogram
to work-up her dizziness. The patient “finally figured out it was the Xanax” anddiscontinued it abruptly after six weeks. Since the patient was on a low dose for a
relatively short period of time, the physician reportedly never mentioned tapering thepatient’s dose. After discontinuing alprazolam, the patient experienced “terrible
insomnia, tremors, night terrors, derealization, depersonalization, panic, anxiety, spots invision, dizziness and heart palpitations.” At the time of the report, the patient had been
completely off alprazolam for two years and stated that the symptoms had diminished,but she still had spots in her vision, increased anxiety and insomnia.
Case 4
FAERS# 6203360, Version 1, Initially received by FDA December 2006
Drug of Interest: Lorazepam
Outcomes: Life threatening, Other serious
A 36-year-old female patient was prescribed lorazepam 0.25 mg twice daily as needed asa sleep aid and to help with occasional anxiety. She was given three refills with the firstprescription and no instructions to follow-up. Four months later, the patient was taking
0.25 mg twice daily and felt that her anxiety had improved so stopped taking the morning
dose. She began to feel such severe withdrawals that she restarted the morning dose.
After speaking with a pharmacist, the patient went back to the prescribing physician to
explain that she was having side effects from decreasing the dose and she was told that“the problem was her and that the correct way to taper Ativan was to cut the total daily
dose in half and she should’ve been fine.” The patient reportedly experienced thefollowing withdrawal symptoms: severe anxiety, panic attacks, heart palpitations,excessive sweating, psychotic thinking, depersonalization, derealization, headaches,
tremors, vision disturbances, hearing problem, loss of appetite and weight loss. The
patient went to a new physician who is helping her slowly discontinue lorazepam. The
patient reported that these symptoms have greatly diminished now that the patient is “ona proper taper.”93
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Reviewer’s comment: Cases 2-4 describe situations where a benzodiazepine wasprescribed for either insomnia or anxiety at low doses. In all three cases, the patients
took the benzodiazepine as directed (or less frequently) and developed symptoms ofdependence. When the patients then expressed concerns to their prescribers, theprescribers believed that the problem must not be the benzodiazepine use because thedoses were low. In all three cases, the patients experienced symptoms consistent withbenzodiazepine withdrawal and required a slow tapering schedule in order tosuccessfully discontinue their respective medications.
In Case 3, similar to Case 1, the patient was not instructed to taper the benzodiazepine.
She may have experienced less severe withdrawal symptoms or no symptoms had she
been instructed to discontinue alprazolam as recommended in the Dosage andAdministration section for Dose Reduction in the alprazolam product labeling:“Because of the danger of withdrawal, abrupt discontinuation of treatment should
be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND
DEPENDENCE).
In all patients, dosage should be reduced gradually when discontinuing therapy orwhen decreasing the daily dosage. Although there are no systematically collected
data to support a specific discontinuation schedule, it is suggested that the daily
dosage be decreased by no more than 0.5 mg every 3 days. Some patients may
require an even slower dosage reduction.
In any case, reduction of dose must be undertaken under close supervision andmust be gradual. If significant withdrawal symptoms develop, the previous dosing
schedule should be reinstituted and, only after stabilization, should a less rapid
schedule of discontinuation be attempted. In a controlled postmarketing
discontinuation study of panic disorder patients which compared thisrecommended taper schedule with a slower taper schedule, no difference wasobserved between the groups in the proportion of patients who tapered to zero
dose; however, the slower schedule was associated with a reduction in symptoms
associated with a withdrawal syndrome. It is suggested that the dose be reduced
by no more than 0.5 mg every 3 days, with the understanding that some patients
may benefit from an even more gradual discontinuation. Some patients may prove
resistant to all discontinuation regimens.” [7]In Case 4, she was given three refills with her first prescription for lorazepam and no
instructions for follow-up. Her adverse experiences with lorazepam may have been
avoided if she was seen two to four weeks after receiving the initial prescription toevaluate the need for further treatment with lorazepam. The Warning section for Physicaland Psychological Dependence in the lorazepam product labeling states:“In general, benzodiazepines should be prescribed for short periods only (e.g., 2
to 4 weeks). Extension of the treatment period should not take place without
reevaluation of the need for continued therapy. Continuous long-term use of
product is not recommended. Withdrawal symptoms (e.g., rebound insomnia) can
appear following cessation of recommended doses after as little as one week of94
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(b) (4)prescriptions in 2018 5. Solid oral formulations of benzodiazepines were(b) (4)predominantly dispensed to adult female patients.
of patients aged 18 years
or older are estimated to have received a benzodiazepine prescription for three months or
longer. From 2014 through 2018, alprazolam, diazepam, lorazepam, and clonazepam
were the most-frequently dispensed benzodiazepines.
Epidemiologic data
Our examination of available data suggest that benzodiazepine misuse, abuse andassociated morbidity and mortality are substantial but primarily occur in the context ofpolysubstance use.
•

Annually from 2015 to 2018, approximately 5.4 million (2.0%) U.S. individuals aged
12 and older are estimated to have misused or abused benzodiazepines. The highest
prevalence was in the 18-25 year-old age group, in which almost half of past-year
benzodiazepine users reported misusing or abusing the drugs. The most commonly
reported reasons for benzodiazepine misuse or abuse were to “relax or relievetension” (46.3%), “help with sleep” (22.4%), “get high or [respondent] was hooked”(11.8%), “help with emotions” (10.5%), and “experiment or to see what the drug islike” (5.7%).

•

Among 12th graders, estimated nonmedical use of several commonly usedbenzodiazepines has declined over the past decade, paralleling downward trends inuse of multiple other prescription and illicit drugs in this group.

•

In 2016, the nationally estimated number of ED visits due to nonmedical use of
benzodiazepines (n=167,845), was higher than the corresponding estimate forprescription opioids (n=129,863), although a relatively small proportion of visits
involved benzodiazepines alone—13.9% (n=23,335) compared to 31.2% (n=40,499)
for visits due to prescription opioid nonmedical use.

•

There was a high frequency of exposure calls to U.S. poison centers involving
benzodiazepine misuse or abuse, and trends were generally consistent withprescribing trends. The annual number of exposure calls involving a benzodiazepine
misuse or abuse increased from 10,156 in 2009 to 10,738 in 2011, then decreased to
8,761 in 2017. However, the observed declines in benzodiazepine exposure calls
were driven by calls with minor clinical effects, whereas benzodiazepines exposure
calls with more severe medical outcomes increased across the study period.
Approximately 63% of benzodiazepine misuse/abuse calls in 2017 involved multiple
substances—most commonly prescription opioids, alcohol, or stimulants—andmedical outcomes in these cases are more severe than in cases involving
benzodiazepines alone. The distribution of medical outcome severity in singlesubstance misuse/abuse calls was similar across the five most commonly prescribedbenzodiazepines.

5

Estimates of dispensed prescriptions were affected by a methodology change in the underlying data
source to account for prescription voids and reversals, resulting in a trend break between estimates prior to(b) (4)2017. Estimates for 2017 and 2018 wereapproximately (b)(4) due to the change in methodology.

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•Upon analysis of 15,779 single-substance benzodiazepine exposure calls reported to
U.S. poison centers specifically involving abuse between 2009-2017, 15% (n=2,394)
reported moderate-to-severe medical outcomes in patients with clinical effects related
to the exposure. The most commonly reported related clinical effects andcorresponding frequency in these exposures included drowsiness/lethargy (76%),slurred speech (24%), confusion (14.1%), tachycardia (13.3%), hypotension (13.3%),
and ataxia (13.1%).

•

Benzodiazepine-involved poisoning deaths increased from 1,298 in 2010 to 11,537 in
2017. The proportion of deaths due to benzodiazepines alone was small anddecreased over this period, from 8.6% in 2000 to 2.7% in 2017. From 2013-2017,55.4% of benzodiazepine-involved fatal poisonings also involved prescription
opioids, but only 9.7% involved benzodiazepines and prescriptions opioids without
mention of any additional substances.

•

We identified no high-quality longitudinal studies assessing the risk of addiction
associated with benzodiazepine use. However, in 2017, 1.2% of admissions(n=10,316) to publicly-funded substance use disorder treatment programs indicatedthat benzodiazepines were the primary drug of abuse, compared to 3.1% for opioid
analgesics. An additional 7.3% and 9.8% of admissions indicated benzodiazepines as
the secondary and tertiary drug of abuse, respectively. In one published analysis of
NSDUH data from 2015-2016, an estimated 0.5 million people ages 18 and older
annually reported misuse or abuse of benzodiazepines, did not report misuse or abuseof other sedatives, hypnotics, or anxiolytics, and met the criteria for Sedative,
Hypnotic, or Anxiolytic Use Disorder, per the Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition (DSM-IV). Although these data cannot be used toestimate the risk of benzodiazepine addiction associated with use of these
medications, they indicate that both primary benzodiazepine use disorders andpolysubstance addiction involving benzodiazepines do occur.

FAERS Data: High-level Overview
The high-level overview of FAERS reports revealed that, after exclusion of those reports
also included in NPDS to avoid duplicate counts with DEPI’s NPDS analysis, almost
44,000 reports related to benzodiazepine abuse, dependence, or withdrawal were reported
to FDA from the time of approval through June 30, 2019, of which approximately 24%
involved a concomitant opioid. The most frequently reported PTs across the top fourmost frequently reported benzodiazepines (in descending order: alprazolam, diazepam,
lorazepam, clonazepam) were similar and mostly related to overdose, abuse, dependence,or withdrawal. There were slight differences in distribution of PTs across the four drugs,
but no major differences were noted. Sixty percent of all fatal reports involving abenzodiazepine also involved a concomitant opioid, with approximately 3% of fatal
reports involving a benzodiazepine as a single drug substance. The remaining fatal
reports involved a benzodiazepine along with one or more of the following, listed indecreasing order of frequency: alcohol, various antidepressants, acetaminophen,zolpidem and various antipsychotics (See Section 3.8.1 and Table 3.16 for additional

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details). The FAERS findings were congruent with the epidemiologic data, which
demonstrated high levels of benzodiazepine abuse and increased severity of clinicaleffects when benzodiazepines abuse involved other drugs.

DEPENDENCE AND WITHDRAWAL
Epidemiologic Data
From 2009 to 2017, the number of calls to U.S. poison centers for benzodiazepine
withdrawal increased from 263 to 372. A small number of published longitudinal studies
described risk factors for long-term or high-dose benzodiazepine use or dependence.
These included female sex, older age, mental health conditions, and concomitant use ofcertain medications (e.g., antidepressants). However, most of these studies wereconducted in non-U.S. populations and had other limitations.
FAERS Data: Report-level Review
The report-level review of 104 FAERS cases of benzodiazepine as single drug substancesubmitted directly to FDA from patients and healthcare providers (i.e., direct reports)
mostly consisted of reports of dependence or withdrawal occurring with use of abenzodiazepine as prescribed, rather than abuse. Because we limited our search to direct
reports only, there is likely a bias against identifying cases of abuse or illicit use,
especially because most cases in this case series (n=82, 79%) were submitted by thepatients themselves.
We identified dependence and subsequent withdrawal, in some cases with highmorbidity, that developed during therapeutic use of benzodiazepines (clonazepam,
alprazolam, lorazepam, diazepam, triazolam, or oxazepam). Approximately 80% of thecases in this case series described symptoms associated with withdrawal frombenzodiazepines that included mainly central nervous system effects (e.g., insomnia,
increased anxiety or panic attacks, memory impairment, depression), cardiovasculareffects (e.g., heart rate or rhythm fluctuations), and gastrointestinal effects (e.g.,
abdominal pain, nausea, diarrhea). The median time to onset of dependence or tolerance
was within two weeks of initiating use, ranging from one day to four years. The majorityof cases reported a duration of use ranging from months to years, rather than the shortterm use of no more than several weeks currently recommended in some benzodiazepine
product labeling. The median duration of withdrawal symptoms for all benzodiazepines
was approximately 9.5 months and ranged from two weeks to eight years. An important
limitation in the assessment of these cases was the difficulty in differentiating withdrawal
symptoms from potential re-emergence or continuation of symptoms for which the
benzodiazepine was being used. The Drug Abuse and Dependence Section of the current
Xanax product labeling also acknowledges the difficulty of distinguishing withdrawal
and recurrence, especially in patients undergoing dose reduction.
Our analysis of the FAERS dependence and withdrawal cases, coupled with the findingsof prevalent longer-term use and increasing numbers of poison center calls for

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estimates from where the majority of benzodiazepines are dispensed, outpatient retail andmail-order pharmacies. The data captures dispensed prescriptions across all payment
methods and can be trended across time.
The IQVIA NPA and TPT databases are proprietary dynamic data sources; changes to theunderlying source data and projection methodologies have been implemented by the data
vendor over time. 6
Of note, the data obtained from the proprietary databases are estimated prescription
and/or patient counts based on projections of sample prescription claims data andtherefore have some degree of inherent uncertainty. These estimates are not intended tobe representations of exact enumerations and should be interpreted with caution
particularly if they are based on a small sample size. Summarization of projectedprescription estimates may lead to differences in prescription counts due to rounding
attributable to the projection methodology utilized. No statistical tests were performed onthese data.
We focused our analyses primarily on the outpatient retail and mail order pharmacy
settings. Consequently, these national estimates may not be generalized to other settingsof care in which these products are used (i.e. clinics, non-federal hospitals, etc.).
Epidemiologic Data on Benzodiazepine Abuse, Dependence, and Related
Outcomes
4.4.2.1 NPDS
Strengths:
A strength of the NPDS dataset is its ability to record detailed drug exposure informationfrom self-reported information from callers, by using standard procedures for datacollection and management.
Limitations:
NPDS does not contain all cases of misuse/abuse that warrant medical attention, because
not every case generates a call to a PCC. Also, we speculate that people would not call
PCC for withdrawal symptoms, so it is not ideal for surveillance of benzodiazepine
dependence and withdrawal. It is uncertain what fraction of events result in a PCC call,and to what extent this fraction varies over time. The most severe events, resulting in outof-hospital overdose death, may be unlikely to generate a call to a PCC. Therefore, NPDS
may disproportionately fail to capture cases involving drugs with the highest risk of suchfatal overdoses. Calls related to misuse/abuse of benzodiazepines may be affected by theoverall decline in calls to U.S. PCCs in recent years and by changes in the awareness of
the risks and effects of these drugs by medical personnel and the public. Finally, followup and medical outcomes are not available for all calls.

6

Source: IQVIA, National Prescription Audit (NPA). January 2016 - December 2018. Data Extracted April 2019.Files:
VRAF USC Product Combined Guidance Nov 2016 - Dec 20418 FINAL xlsx.;

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4.4.2.2 NEISS-CADESStrengths:
NEISS-CADES has the notable strengths of national representativeness, narrative details
of AE circumstances, and high data quality, due to the rigorous standards for ED medical
chart abstraction.
Limitations:
NEISS-CADES data can be used to calculate national estimates of ED visits for AEs
attributed to medication use, with the limitation that NEISS-CADES excludes cases that
do not result in an ED visit, cases that result in death before or during ED evaluation, andcases of people presenting to the ED due to inadequate therapy or drug withdrawal. The
quality of these surveillance data depends on the completeness and accuracy of medical
record documentation by the healthcare provider and, to be included in NEISS-CADES,
cases require documentation by the healthcare provider that a drug or drug class (e.g.,“benzodiazepine”) was implicated in the ED visit.
4.4.2.3 TEDS
Strengths:
To our knowledge, TEDS is the largest source of nationwide data on the primary,secondary, and tertiary substances abused at SUD treatment admission. Data collection issystematic to comply with mandatory state reporting. These features enable the mostfeasible, approximate estimate of the burden of SUD associated with benzodiazepines
abuse.
Limitations:
TEDS does not draw from a nationally-representative sample of SUD treatment
admissions. So, it cannot estimate the national burden of SUD treatment associated withbenzodiazepines, or the frequency of benzodiazepine abuse. For the same reason, caution
should be used in comparing TED’s estimate of the burden of SUD treatment associatedwith benzodiazepines with that of other drugs or substances. TEDS contains data from all
SUD admissions that are funded by Federal Block Grant funds, state alcohol/drug
agencies, or both; also, some data are from privately-funded admissions to treatment sitesthat receive state funding. TEDS lacks data from centers operated by federal agencies.
4.4.2.4 NVSS-M
Strengths:
National Vital Statistics System Mortality data provide a comprehensive description ofdeaths in the U.S. population. Information on the death certificate is coded by aprofessional who is legally responsible for the registration of the death, and the deathcertificate allows the opportunity for specifying a single underlying cause of death and up
to twenty contributing causes. The death certificate also includes demographic
information, providing valuable information for epidemiologic analyses.
Limitations:

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One important limitation to consider for the use of death certificate data is that variation
exists in the death investigation, including conducting autopsy, interpreting toxicology
results, and determination of which drugs to include on the death certificate [42]. Thisvariation could result in bias for certain populations, such as underreporting for
populations less likely to be suspected of drug overdose and improvements in reporting
could affect trends overtime [42].
4.4.2.5 NSDUHStrengths:
NSDUH is designed to estimate the annual prevalence of misuse and abuse of
benzodiazepines and other drugs and substances among the U.S. civilian, noninstitutionalized population, age 12 and older.
Limitations:Individuals with advanced substance use disorders may be underrepresented, particularly
if they become homeless, incarcerated, or enter a residential treatment facility. Also,these survey results are subject to the inherent limitations of self-reported data, such as
non-response bias, misclassification, and recall bias. In addition, their construct of misuse
and abuse encompasses a broad range of behaviors, including misuse for therapeutic
purposes as well as use of the drug to gain a high or euphoric effect. Finally, the survey
does not collect data on route of administration.
FAERS
Strengths:
This is the first postmarketing review completed that includes a broad search of FAERS
for benzodiazepines and drug abuse, dependence, and withdrawal. Using FAERS, wehave the ability to detect rare, but serious, AEs, especially those that occur soon after
drug exposure. It includes all marketed products, uses, and patient populations for agiven drug or therapeutic biologic product.
Limitations:Because abuse, dependence, and withdrawal with benzodiazepines is a common and awell-known AE, there is a high volume of reports included in this review. Therefore, areport-level analysis of all reports was not feasible. It is important to note that causality
has not been assessed for the high-level overview portion of this review, so conclusions
cannot be drawn regarding the relatedness of these AEs to benzodiazepines.
FAERS is a database containing spontaneous AE reports; therefore, reporting rates areaffected by the following: media attention, litigation (class action lawsuits), nature of theAE, type of drug product and new indications, length of time on market, extent andquality of manufacturer’s surveillance system, and changes in reporting regulations,among others. Because of the spontaneous nature of the reports, incidence of a given AE
cannot be calculated using FAERS data and comparisons between drugs are not accurate.
Additionally, there is no certainty that the reported event was actually due to the product.
FAERS reports do not always contain enough detail to properly evaluate an event.
Therefore, the conclusions that can be made from FAERS reports are highly dependent

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(b) (4), (b) (5)2. Consider a Boxed Warning for all benzodiazepines describing the risks of misuse
and abuse, dependence, withdrawal, addiction, and overdose, and the need for(b) (5)
gradual dose tapering. Suggested language is included as an example below,(b) (4), (b) (5)3. Issue a DSC to accompany any labeling changes(b) (5)

4.

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7

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[29] American Psychiatric Association, in Diagnostic and Statistical Manual of Mental
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[30] J. A. Hermos, M. M. Young, E. V. Lawler, D. Rosenbloom and L. D. Fiore, "Long-term,high-dose benzodiazepine prescriptions in veteran patients with PTSD: influence ofpreexisting alcoholism and drug-abuse diagnoses," J Trauma Stress, pp. 909-14, 2007.
[31] L. Manthey, M. Lohbeck, E. J. Giltay, T. van Veena, F. G. Zitman and B. W. Penninx,"Correlates of benzodiazepine dependence in the Netherlands Study of Depression andAnxiety," Addiction, vol. 107, pp. 2173-2182, 2012.
[32] G. Airagnes, C. Lemogne, A. Renuy, M. Goldberg, N. Hoertel, Y. Roquelaure, F. Limosinand M. Zins, "Prevalence of prescribed benzodiazepine long-term use in the French general
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CONSTANCES cohort," BMC Public Health, 2019.
[33] H. J. Luijendijk, H. Tiemeier, A. Hofman, J. Heeringa and B. H. C. Stricker, "Determinantsof chronic benzodiazepine use in the elderly: a longitudinal study," British Journal of
Clinical Pharmacology, vol. 65, pp. 593-599, 2008.
[34] C. de las Cuevas, E. Sanz and J. de la Fuente, "Benzodiazepines: more "behavioural"
addiction than dependence," Psychopharmacology (Berl), pp. 297-303, 2003.
[35] A. J. Mol, W. J. Gorgels, R. C. Oude Voshaar, M. H. Breteler, A. J. van Balkom, E. H. vande Lisdonk, C. C. Kan and F. G. Zitman, "Assocaitions of benzodiazepine craving withother clinical variables in a population of general practive patients," Comprehensive
Psychiatry, vol. 46, pp. 353-360, 2005.
[36] R. J. Peters, A. F. Meshack, S. H. Kelder, P. Webb, D. Smith and K. Garner, "Alprazolam(Xanax) use among southern youth: beliefs and social norms concerning dangerous rides on"handlebars"," J Drug Education, vol. 37, pp. 417-428, 2007.
[37] K. D. Murphy, S. Lambert, S. McCarthy, L. J. Sahm and S. Byrne, ""You don't feel": Theexperience of youth benzodiazepine misuse in Ireland," Journal of Psychoactive Drugs, vol.
50, pp. 121-128, 2017.
[38] "FDA Adverse Events Reporting System (FAERS) Public Dashboard," 30 September 2019.
[Online]. Available: https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e40135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis. [Accessed
30 January 2020].
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[42] H. Hedegaard, B. A. Bastian, J. P. Trinidad, M. Spencer and M. Warner, "Drugs mostfrequently involved in drug overdose deaths: United States, 2011-2016," National Vital
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[43] L. Manthey, E. J. Giltay, T. van Veen, A. Knuistingh Neven, F. G. Zitman and B. W.
Penninx, "Determinants of initiated and continued benzodiazepine use in the Netherlands
Study of Depression and Anxiety," J Clin Psychopharmacol, vol. 31, pp. 774-779, 2011.
[44] L. Wingard, H. Taipale, J. Reutfors, A. Westerlund, R. Boden, J. Tiihonen, A. Tanskanen
and M. Andersen, "Initiation and long-term use of benzodiazepines and Z-drugs in bipolar
disorder," Bipolar Disorders, vol. 20, pp. 634-646, 2018.
[45] N. Takeshima, Y. Ogawa, Y. Hayasaka and T. A. Furukawa, "Continuation anddiscontinuation of benzodiazepine prescriptions: a cohort study based on a large claims
database in Japan," Psychiatry Research, vol. 237, pp. 201-207, 2016.
[46] P. Voyer, M. McCubbin, D. Cohen, S. Lauzon, J. Collin and C. Boivin, "Unconventional
indicators of drug dependence among elderly long-term users of benzodiazepines," Issues in
Mental Health Nursing, vol. 25, pp. 603-628, 2009.
[47] M. Balestrieri, G. Marcon, F. Samani, M. Marini, E. Sessa, U. Gelatti and F. Donato,"Mental disorders associated with benzodiazepine use among older primary care attenders-a regional survey," Soc Psychiatry Psychiatr Epidemiol, pp. 308-15, 2005.
[48] I. Fride Tvete, T. Bjørner and T. Skomedal, "Risk factors for excessive benzodiazepine use
in a working age population: a nationwide 5-year survey in Norway," Scandinavian journalof primary health care, pp. 252-259, 2015.
[49] C. A. Fontanella, J. V. Campo, G. S. Phillips, D. L. Hiance-Steelesmith, H. A. Sweeney, K.
Tam, D. Lehrer, R. Klein and M. Hurst, "Benzodiazepine Use and Risk of Mortality Among
Patients With Schizophrenia: A Retrospective Longitudinal Study," Journal of ClinicalPsychiatry, pp. E661-E667, 2016.
[50] L. D. Johnston, R. A. Miech, P. M. O'Malley, J. G. Bachman, J. E. Schulenberg and M. E.
Patrick, "Monitoring the Future national survey results on drug use 1975-2018: Overview,
key findings on adolescent drug use," 2019.
[51] C. S. Hwang, E. M. Kang, C. J. Kornegay, J. A. Staffa, C. M. Jones and J. K. McAninch,"Trends in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.," Am
J Prev Med, vol. 51, no. 2, pp. 151-160, 2016.

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** Due to methodology changes, there was a data break between 2016 and 2017 data. Unique patient counts may not be added acrosstime periods due to the possibility of double counting those patients who are receiving treatment over multiple periods in the study.
Furthermore, patient age subtotals may not sum exactly due to patients aging during the study period and may be counted more thanonce in the individual age categories. For this reason, summing across time periods or patient age bands is not advisable and will result inoverestimates of patient counts.

APPEARS THIS WAY ON
ORIGINAL

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Appendix A.2: Drug Utilization Database Descriptions
IQVIA National Sales Perspectives™: Retail and Non-Retail
The IQVIA National Sales Perspectives™ measures the volume of drug products, both prescription andover-the-counter, and selected diagnostic products moving from manufacturers into various outlets within
the retail and non-retail markets. Volume is expressed in terms of sales dollars, eaches, extended units, andshare of market. These data are based on national projections. Outlets within the retail market include thefollowing pharmacy settings: chain drug stores, independent drug stores, mass merchandisers, food stores,
and mail service. Outlets within the non-retail market include clinics, non-federal hospitals, federal
facilities, HMOs, long-term care facilities, home health care, and other miscellaneous settings.
IQVIA National Prescription Audit™
The IQVIA National Prescription Audit™ (NPA) measures the “retail outflow” of prescriptions, or the rate
at which drugs move out of retail pharmacies, mail service houses, and long-term care facilities into thehands of consumers via formal prescriptions in the U.S. The NPA audit measures what is sold to thepatient. Data for the NPA audit is a national level estimate of the drug activity from these three channels.
NPA receives over 3.8 billion retail prescription claims per year, captured from a sample of the universe of
approximately 58,900 retail pharmacies throughout the U.S. The pharmacies in the database account formost retail pharmacies and represent ~92% of retail prescriptions dispensed nationwide. The type ofpharmacies in the sample are a mix of independent, retail, chain, mass merchandisers, and food stores withpharmacies, and include prescriptions from cash, Medicaid, commercial third-party and Medicare Part-D
prescriptions. Data is also collected from approximately 60 – 86% (varies by class and geography) of mailservice pharmacies and approximately 75 – 83% of long-term care pharmacies. Data are available in
IQVIA’s business intelligence tool SMART for 72-rolling months. Each month, NPA is updated to include
the most recent data month and made available between the 12-18 days after the end of the month.
Due to the changing pharmaceutical marketplace, IQVIA has implemented changes to its prescription
database to manage prescription voids, reversals, and abandonments that span multiple weeks. Beginning inJanuary 2019, IQVIA has projected published prescription volumes dispensed from the retail pharmacies
based on sold date, instead of date of adjudication (i.e., fill date). Projected estimates have been adjusted
and restated in the database back to January 2017, data prior to 2017 remain unadjusted. As a result, a
trend break occurs between 2016 and 2017 prescription volumes dispensed from the retail pharmacies, anychanges over time must be interpreted in the context of the changes in the underlying data andmethodology.
Dispensed prescription estimates are nationally projected based on a sample of prescriptions claims.
Summarization of projected prescription estimates may lead to differences in prescription count due torounding attributable to the projection methodology utilized. No statistical tests were performed on theseestimates to determine statistically significant changes over time. Therefore, all changes over time should
be considered approximate, and may be due to random error.
NPA New to Brand (NPA NTB) provides enhanced visibility to the volume of a patient’s true, first-time
use of a brand by using IQVIA’s patented patient de-identification algorithm to determine if a patient has
filled a prescription for that brand or another brand within the market within a predetermined look backperiod (typically 12 months, shorter for acute markets).
Symphony Health Integrated Dataverse IDV®
IDV (Integrated Dataverse) from Symphony Health contains longitudinal patient data sources that capture
adjudicated prescription, medical, and hospital claims across the United States for all payment types,
including commercial plans, Medicare Part D, cash, assistance programs, and Medicaid. The IDV contains
over 10 billion prescriptions claims linked to over 280 million unique prescription patients of with anaverage of 5 years of prescription drug history. Claims from hospital and physician practices include over
190 million patients with CPT/HCPCS medical procedure history as well as ICD-9/10 diagnosis history ofwhich nearly 180 million prescription drug patients are linked to a diagnosis. The overall sample

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represents over 65,000 pharmacies, 1,500 hospitals, 800 outpatient facilities, and 80,000 physician
practices.
IQVIA Total Patient Tracker™ (TPT)IQVIA Total Patient Tracker (TPT) is a national-level projected service designed to estimate the total
number of unique (non-duplicated) patients across all drugs and therapeutic classes in the retail outpatientsetting from U.S. retail pharmacies. Data are available back to January 2002 and are available 20 days after
the close of the month. TPT uses prescription activity as part of its projection and integrates informationfrom pharmacies and payers to eliminate duplicate patients and multiple prescription fills, producing quick
and reliable unique patient counts. IQVIA has 92% coverage and a sample of ~58,900 retail pharmacies.
IQVIA captures about 3.8 billion transactions annually. TPT is projected to the known universe of retailpharmacies.
Due to the changing pharmaceutical marketplace, IQVIA has implemented changes to its prescription
database, National Prescription Audit™ (NPA), to manage prescription voids, reversals, and abandonmentsthat span multiple weeks. Beginning in January 2019, IQVIA has projected published prescription volumes
dispensed from the retail pharmacies based on sold date, instead of date of adjudication (i.e., fill date).
Because TPT patient data are derived from NPA prescription data, projected patient estimates have beenadjusted and restated in the database back to January 2017, data prior to 2017 remain unadjusted. As aresult, a trend break occurs between 2016 and 2017 patient estimates who received prescriptions dispensed
from the retail pharmacies; any changes over time must be interpreted in the context of the changes in theunderlying data and methodology.
Patient estimates are nationally projected based on a sample of prescriptions claims. Summarization ofprojected patient estimates across age groups or time periods may lead to differences in patient count due torounding attributable to the projection methodology utilized.
Unique patient counts may not be added across time periods due to the possibility of double counting thosepatients who are receiving treatment over multiple periods in the study. Furthermore, patient age subtotals
may not sum exactly due to patients aging during the study period and may be counted more than once in
the individual age categories. For this reason, summing across time periods or patient age bands is notadvisable and will result in overestimates of patient counts.
Of note, the estimated prescription and/or patient counts provided are based on projections of sample
prescription claims data and therefore have some degree of inherent sampling error. These estimates are notintended to be representations of exact enumerations and should be interpreted with caution particularly ifthey are based on a small sample size. In addition, the data cannot be validated due to lack of access to
medical records in the data sources.

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APPENDIX B. AMERICAN ASSOCIATION OF POISON CONTROL CENTERS
Table B1. AAPCC/NPDS generic codes product codes
Generic codes
Generic code

Description(b) (4)

Benzodiazepines

Table B2. Product codes
Drug

Product code
Note: These product codes must be redacted for public release

Alprazolam

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Drug

Product code
Note: These product codes must be redacted for public release(b) (4)

Clonazepam

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Drug

Product code
Note: These product codes must be redacted for public release

Diazepam

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Drug

Product code
Note: These product codes must be redacted for public release(b) (4)(b) (4)

Lorazepam

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Drug

Product code
Note: These product codes must be redacted for public release(b) (4)(b) (4)

Temazepam

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Drug

Product code
Note: These product codes must be redacted for public release(b) (4)

Table B3. AAPCC NPDS Definitions of Exposure Reasons
REASON:
Unintentional: An unintentional exposure results from an unforeseen or unplanned event. For
example, a child gaining access to a toxic substance, when it is obvious the child did not realize
the danger of the action, is an unintentional exposure. The following eight coding options areavailable for unintentional exposures. (Includes sub-categories: General; Environmental;
Occupational; Therapeutic Error; Misuse; Bite/Sting, Food Poisoning; Unknown)
Intentional: A purposeful action results in an exposure. The following four categories relate tointentional exposures. (Includes sub-categories: Suspected Suicidal; Misuse; Abuse; Unknown)
Intentional exposure
reasons

Definition“An exposure resulting in the inappropriate use of a substance forself-harm or self-destruction or manipulative reasons”“An exposure resulting from the intentional improper or incorrect
use of a substance where the victim was likely attempting to gain a
Abusehigh, euphoric effect or some other psychotropic effect”, including
recreational use of a substance for any effect“An exposure resulting from the intentional improper or incorrect
Misuseuse of a substance for reasons other than the pursuit of a
psychotropic effect”
Exposures that are deemed to be intentional although the specificUnknown
motive is undetermined
Source: American Association of Poison Control Centers. National Poison Data System(NPDS) Data Dictionary. Version 2016.07.11. July 11, 2016
Suspected Suicides

Adverse Reaction: This category is used to monitor adverse reactions (experiences) to avariety of products, including drugs, foods, cosmetics and industrial or household
chemicals. (Includes sub- categories: Drug; Food; Other)
Other/Unknown: This category is used when the reason for the exposure cannot be determined or
if no other category is appropriate. (Includes sub-categories: Contaminant/Tampering; Malicious;
Withdrawal; Unknown)
Other/Unknown: This category is used when the reason for the exposure cannot be determined or
if no other category is appropriate. (Includes sub-categories: Contaminant/Tampering;
Malicious; Withdrawal; Unknown)

MEDICAL OUTCOME:
No Effect: The patient developed no symptoms (clinical effects) as a result of the exposure.
Follow-up is required to make this determination unless the initial poison center call occurs
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sufficiently long enough after the exposure that the poison center is reasonably certain no
effects will occur.
Minor Effect: The patient exhibited some symptoms as a result of the exposure, but they wereminimally bothersome to the patient. The symptoms usually resolve rapidly and often involve
skin or mucous membrane manifestations. The patient has returned to a pre-exposure state ofwell-being and has no residual disability or disfigurement. Follow-up is required to make thisdetermination unless the initial poison center call occurs sufficiently long enough after the
exposure that there is reasonable certainty that the clinical effect(s) will not worsen.
Symptomatic patients must be followed until symptoms have resolved or nearly resolved,
unless the residual symptoms are anticipated to be long-term and of minimal clinicalsignificance.
Moderate Effect: The patient exhibited symptoms as a result of the exposure which are more
pronounced, more prolonged or more of a systemic nature than minor symptoms. Usually someform of treatment is or would have been indicated. Symptoms were not life-threatening, andthe patient has returned to a pre-exposure state of well-being with no residual disability or
disfigurement. Follow-up is required to make this determination unless the initial regional
poison center call occurs sufficiently long enough after the exposure that there is reasonablecertainty that the clinical effect(s) will not get worse. Symptomatic patients must be followed
until symptoms have resolved or nearly resolved, unless the residual symptoms are anticipatedto be long-term and of minimal clinical significance.
Major Effect: The patient has exhibited symptoms as a result of the exposure which were lifethreatening or resulted in significant residual disability or disfigurement. Follow-up is required
to make this determination unless the initial poison center call occurs sufficiently long enoughafter the exposure that there is reasonable certainty the clinical effect(s) will not get worse.
Symptomatic patients must be followed until symptoms have resolved or nearly resolved,
unless the symptoms are anticipated to be long-term or permanent.
Death: The patient died as a result of the exposure or as a direct complication of the exposure
where the complication was unlikely to have occurred had the toxic exposure not preceded thecomplication. Only include those deaths which are probably or undoubtedly related to the
exposure. A fatality verification is required. Also include deaths in which the exposure was acontributing factor in the death. For deaths determined to be unrelated to the exposure (those inwhich the most clinically significant clinical effects are coded as unrelated) the outcome iscoded as “Unrelated effect” (the exposure was probably not responsible for the effect[s]).
Other – Includes sub-categories:
Case not followed to a known outcome: In some circumstances it is not appropriate or possible tofollow a patient to a reasonably certain medical outcome. In these instances, choose one of thefollowing:Not followed, judged as nontoxic exposure: The patient was not followed, per clinical judgment
the exposure was likely to be nontoxic because the agent involved was nontoxic. The amount
implicated in the exposure was insignificant (nontoxic), and/or the route of exposure wasunlikely to result in a clinical effect. If this response is selected, there must be reasonablecertainty that the patient will not experience
any clinical effect from the exposure. Cases that refused follow-up if the exposure was judged as
nontoxic may also be included.
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APPENDIX C. NATIONAL ELECTRONIC INJURY SURVEILLANCE SYSTEM–COOPERATIVE ADVERSE DRUG EVENT SURVEILLANCE
Table C1. Emergency Department Visits due to Adverse Events Involving Benzodiazepines,
by Patient Characteristics, 2016-2017a
Nonmedical Use of Benzodiazepinesb
Patient
Characteristics

Cases
No.

Annual Estimate
No.
Patient age (years)c-1,215d%

95% CI-1.0d-(0.3-1.7)

<5
5-14

0
50

15-24

902

30,92926(20.6-31.4)

25-34

1,004

34,23928.8(24.8-32.8)

35-44

562

18,07615.2(12.8-17.5)

45-54

512

17,27814.5(12.5-16.5)

55-64
381
12,74010.7(8.7-12.7)
65-74
104
3,640
3.1
(2.0-4.1)
≥75
22
838f
0.7
(0.3-1.1)aData are from the National Electronic Injury Surveillance System-Cooperative Adverse Drug
Event Surveillance project, CDC. Estimates based on <20 cases or total estimates <1,200 are
considered statistically unstable and are not shown (--).
b
Includes abuse, therapeutic misuse, and overdoses without documentation of therapeutic
intent, self-harm, abuse, or misuse.
cMissing age for 2 cases of nonmedical use.
d
Coefficient of variation >30%.
Source: Moro RN, Geller AI, Weidle NJ, et al. Emergency Department Visits Involving
Benzodiazepines, United States, 2016-2017 (In Press).

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Table C2. Emergency Department Visits due to Adverse Events Involving Benzodiazepines,by Clinical Manifestations
Nonmedical use of Benzodiazepines
Annual Estimate

Manifestations
No.

%

95% CI

Cardiorespiratory arrest /28,741
24.2(17.7-30.6)
unresponsiveness
Altered mental status
52,75044.3(39.0-49.6)
Presyncope / syncope / dyspnea / fall
6,054
5.1
(3.7-6.5)
Psychiatric or other central nervous
4,346
3.7
(2.7-4.6)
system effectCardiovascular effect
1,220
1.0
(0.6-1.5)
Other manifestations
2,742
2.3
(1.6-3.0)
No documented clinical manifestations
23,15719.5(14.3-24.6)
aData are from the National Electronic Injury Surveillance System-Cooperative
Adverse Drug Event Surveillance project, CDC. Estimates based on <20 cases or
total estimates <1,200 are considered statistically unstable and are not shown (-).Clinical manifestations were categorized in a mutually exclusive and hierarchicalmanner based on severity (e.g., a case involving confusion and blurred vision
would be classified as altered mental status based on documentation of confusion).
b
Coefficient of variation >30%.
Source: Moro RN, Geller AI, Weidle NJ, et al. Emergency Department Visits Involving
Benzodiazepines, United States, 2016-2017 (In Press).

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APPENDIX D. NATIONAL VITAL STATISTICS SYSTEM-MORTALITY
Table D1. Number of all benzodiazepine-related deaths and single drug substancebenzodiazepine deaths, where underlying cause of death is drug poisoning a, 2000-2017,
NVSS-MYear

All benzodiazepine-related deaths

Benzodiazepine only deaths(single drug)

2000

1298

112

2001

1594

120

2002

2022

136

2003

2248

132

2004

2627

149

2005

3084

162

2006

3835

214

2007

4500

194

2008

5010

251

2009

5567

206

2010

6497

240

2011

6872

254

2012

6524

246

2013

6973

253

2014

7945

280

2015

8791

279

2016

10684

328

2017

11537

308

TOTAL

97608

3864

a

where underlying cause of death is drug poisoning (X40-X44, X60-X64, X85, Y10-Y14)

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Table D2. Number of all benzodiazepine-, prescription opioid-, heroin- or synthetic opioidrelated deaths, where underlying cause of death is drug poisoning a, 2000-2017, NVSS-M
Year

All
benzodiazepinerelated deaths

All prescription
opioid-related
deathsAll heroinrelated
deathsAll synthetic opioidrelated deaths

2000

1298

3785

1842

782

2001

1594

4770

1779

957

2002

2022

6483

2089

1295

2003

2248

7461

2080

1400

2004

2627

8577

1878

1664

2005

3084

9612

2009

1742

2006

3835

11589

2088

2707

2007

4500

12796

2399

2213

2008

5010

13149

3041

2306

2009

5567

13523

3278

2946

2010

6497

14583

3036

3007

2011

6872

15140

4397

2666

2012

6524

14240

5925

2628

2013

6973

14145

8257

3105

2014

7945

14838

10574

5544

2015

8791

15281

12989

9580

2016

10684

17087

15469

19413

2017

11537

17029

15482

28466

TOTAL

97608

214088

98612

92421

a

where underlying cause of death is drug poisoning (X40-X44, X60-X64, X85, Y10-Y14)

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Table D3. Number of single drug substance a benzodiazepine-related deaths andbenzodiazepine with prescription opioid-, heroin- or synthetic opioid-related deaths, where
underlying cause of death is drug poisoning b, 2000-2017, NVSS-M
Years

Benzodiazepine
only

Benzodiazepine
andprescription opioid
only

Benzodiazepine
and heroin only

Benzodiazepine andsynthetic opioid
only

2000

112

94

9

15

2001

120

143

10

14

2002

136

179

16

13

2003

132

212

19

21

2004

149

317

16

23

2005

162

402

28

37

2006

214

571

22

50

2007

194

666

40

55

2008

251

719

45

69

2009

206

849

68

58

2010

240

1115

56

77

2011

254

1131

105

68

2012

246

1032

178

59

2013

253

854

223

73

2014

280

891

320

126

2015

279

924

355

193

2016

328

993

371

413

2017

308

792

250

662

11884

2131

2026

TOTAL 3864
aDrug substances: T36.0 to T50.9; does not include alcohol (T51.0)bwhere underlying cause of death is drug poisoning (X40-X44, X60-X64, X85, Y10-Y14)

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Table D4. Average annual rate of deaths involving benzodiazepines among deaths with
underlying cause of death due to drug poisoninga, per 1,000,000 persons b, by age group, US
Residents, 2013-2017

Age Group

Benzodiazepine Benzodiazepine
as single drug
and prescription
Benzodiazepine substance c
opioids

Benzodiazepines and drug
substance other thanprescription opioids

Rates per 1,000,000 population
<10

0.079

0.005

0.040

0.035

10-19

3.447

0.086

1.647

1.714

20-39

43.8920.973

21.49021.43040-5950.1601.692

30.331

18.13760-64

29.4331.346

18.241

9.846

65+
8.470
0.667
4.688
3.115
a
drug poisoning underlying cause of death ICD-10 codes: X40-X44, X60-X64, X85, Y10-Y14b
Denominator populations: age <10: n=201,750,486; age 10-19: n=208,864,296; age 20-39: n=434,955,026;
age 40-59: n=424,278,541; age 60-64: n=95,063,029; age 65+: n=238,493,906; from:https://wonder.cdc.gov/Bridged-Race-v2018.HTMLcSingle drug substance defined by ICD-10 codes T36.0 to T50.9, does not involve alcohol (T51.0)

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"pooled analysis"[tw] OR crossover[tw] OR “meta-analysis”[tw] OR “meta analysis”[tw] OR incidence[tw] OR prevalence[tw] OR risk[tw] OR
incidence[tw] OR longitudinal[tw] OR prospective[tw] OR “risk factors”[tw] OR “risk factor”[tw] OR “natural history”[tw])NOT (“randomized control trial”[tw] OR “randomized-control trial”[tw] OR “randomized control trials”[tw] OR “randomized-control trials”[tw]OR “randomized controlled trial”[tw] OR “randomized controlled trials”[tw] OR “randomized-controlled trial”[tw] OR “randomized-controlled
trials”[tw] OR “randomised control trial”[tw] OR “randomised-control trial”[tw] OR “randomised control trials”[tw] OR “randomised-control
trials”[tw] OR “randomised controlled trial”[tw] OR “randomised controlled trials”[tw] OR “randomised-controlled trial”[tw] OR “randomisedcontrolled trials”[tw] OR RCT[tw] OR “randomized trial”[tw] OR “randomised trial”[tw] OR “randomized control”[tw] OR “randomised
control”[tw] OR “cluster-randomized trial”[tw] OR “cluster-randomised trial”[tw] OR “randomized double-blind”[tw] OR “clinical trial”[tw] OR“clinical trials”[tw] OR “clinical study”[tw] OR “clinical studies”[tw] OR “clinical conference”[tw] OR “clinical conferences”[tw] OR “openlabel”[tw] OR “open-label”[tw] OR “phase I”[tw] OR “phase 1”[tw] OR “phase II”[tw] OR “phase 2”[tw] OR “phase III”[tw] OR “phase 3”[tw] OR
autobiography[tw] OR biography[tw] OR “patient education handout”[tw] OR webcast[tw])NOT (cell[tw] OR "cell line"[tw] OR cellular[tw] OR tissue[tw] OR "in vitro"[tw] OR “in vivo”[tw] OR spectroscopic[tw] OR spectrometer[tw] OR
spectrophotometry[tw] OR "transformation products"[tw] OR "gene variants"[tw] OR plant[tw] OR pharmacokinetic[tw] OR
pharmacodynamic[tw] OR microscopy[tw] OR chromatography[tw] OR “mass spectrometry”[tw] OR “gene expression”[tw])NOT (animals[tiab] OR animal[tiab] OR "Pogona vitticeps"[tiab] OR mice[tiab] OR mus[tiab] OR mouse[tiab] OR murine[tiab] ORwoodmouse[tiab] OR rats[tiab] OR rat[tiab] OR murinae[tiab] OR muridae[tiab] OR cottonrat[tiab] OR cottonrats[tiab] OR hamster[tiab] OR
hamsters[tiab] OR cricetinae[tiab] OR rodentia[tiab] OR rodent[tiab] OR rodents[tiab] OR pigs[tiab] OR pig[tiab] OR swine[tiab] ORswines[tiab] OR piglets[tiab] OR piglet[tiab] OR boar[tiab] OR boars[tiab] OR "sus scrofa"[tiab] OR ferrets[tiab] OR ferret[tiab] OR polecat[tiab]
OR polecats[tiab] OR "mustela putorius"[tiab] OR "guinea pigs"[tiab] OR "guinea pig"[tiab] OR cavia[tiab] OR callithrix[tiab] OR marmoset[tiab]
OR marmosets[tiab] OR cebuella[tiab] OR hapale[tiab] OR octodon[tiab] OR chinchilla[tiab] OR chinchillas[tiab] OR gerbillinae[tiab] OR
gerbil[tiab] OR gerbils[tiab] OR jird[tiab] OR jirds[tiab] OR merione[tiab] OR meriones[tiab] OR rabbits[tiab] OR rabbit[tiab] OR hares[tiab] ORhare[tiab] OR diptera[tiab] OR flies[tiab] OR fly[tiab] OR dipteral[tiab] OR drosphila[tiab] OR drosophilidae[tiab] OR cats[tiab] OR cat[tiab] OR
carus[tiab] OR felis[tiab] OR nematoda[tiab] OR nematode[tiab] OR nematoda[tiab] OR nematode[tiab] OR nematodes[tiab] ORsipunculida[tiab] OR dogs[tiab] OR dog[tiab] OR canine[tiab] OR canines[tiab] OR canis[tiab] OR sheep[tiab] OR sheeps[tiab] OR mouflon[tiab]
OR mouflons[tiab] OR ovis[tiab] OR goats[tiab] OR goat[tiab] OR capra[tiab] OR capras[tiab] OR rupicapra[tiab] OR chamois[tiab] OR
haplorhini[tiab] OR monkey[tiab] OR monkeys[tiab] OR anthropoidea[tiab] OR anthropoids[tiab] OR saguinus[tiab] OR tamarin[tiab] ORtamarins[tiab] OR leontopithecus[tiab] OR hominidae[tiab] OR ape[tiab] OR apes[tiab] OR pan[tiab] OR paniscus[tiab] OR "pan paniscus"[tiab]
OR bonobo[tiab] OR bonobos[tiab] OR troglodytes[tiab] OR "pan troglodytes"[tiab] OR gibbon[tiab] OR gibbons[tiab] OR siamang[tiab] ORsiamangs[tiab] OR nomascus[tiab] OR symphalangus[tiab] OR chimpanzee[tiab] OR chimpanzees[tiab] OR prosimians[tiab] OR "bushbaby"[tiab] OR prosimian[tiab] OR "bush babies"[tiab] OR galagos[tiab] OR galago[tiab] OR pongidae[tiab] OR gorilla[tiab] OR gorillas[tiab] OR

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Returned 1,012 results('benzodiazepine':ti OR 'benzodiazepines':ti OR 'alprazolam':ti OR 'xanax':ti OR 'chlordiazepoxide':ti OR 'librium':ti OR 'librax':ti OR'clobazam':ti OR 'onfi':ti OR 'clonazepam':ti OR 'klonopin':ti OR 'clorazepate':ti OR 'tranxene':ti OR 'T-tab':ti OR 'gen-xene':ti OR 'diazepam':ti
OR 'diastat':ti OR 'acudial':ti OR 'valium':ti OR 'estazolam':ti OR 'prosom':ti OR 'flurazepam':ti OR 'dalmane':ti OR 'dalmadon':ti OR'lorazepam':ti OR 'ativan':ti OR 'oxazepam':ti OR 'serax':ti OR 'quazepam':ti OR 'doral':ti OR 'temazepam':ti OR 'restoril':ti OR 'triazolam':ti OR'halcion':ti OR 'midazolam':ti OR 'versed':ti OR 'bromazepam':ti OR 'flunitrazepam':ti OR 'rohypnol'/exp OR 'rohypnol') AND ('substancerelated disorders'/exp OR 'substance-related disorders' OR ('substance-related':ti,ab AND 'disorders':ti,ab) OR 'substance-relateddisorders':ti,ab OR misuse:ti,ab OR 'nonmedical use':ti,ab OR 'non-medical use':ti,ab OR 'nmu':ti,ab OR 'nonmedical abuse':ti,ab OR'recreational use':ti,ab OR abuse:ti,ab OR 'behavior, addictive'/exp OR 'behavior, addictive' OR ('behavior':ti,ab AND 'addictive':ti,ab) OR'addictive behavior':ti,ab OR 'addiction':ti,ab OR dependence:ti,ab OR 'biological dependence':ti,ab OR 'drug overdose'/exp OR 'drug
overdose' OR (drug:ti,ab AND overdose:ti,ab) OR 'drug overdose':ti,ab OR 'overdose':ti,ab OR 'death'/exp OR death OR death:ti,ab OR
mortality:ti,ab) AND ('systematic review':ti,ab OR cohort:ti,ab OR 'matched-cohort':ti,ab OR 'matched cohort':ti,ab OR 'case-control':ti,ab OR'cross sectional':ti,ab OR 'cross-sectional':ti,ab OR survey:ti,ab OR observational:ti,ab OR 'prevalence study':ti,ab OR 'longitudinal study':ti,abOR 'before-after study':ti,ab OR 'pre-intervention':ti,ab OR 'post-intervention':ti,ab OR 'pre-post':ti,ab OR 'real world':ti,ab OR 'realworld':ti,ab OR 'interrupted time-series':ti,ab OR 'interrupted time series':ti,ab OR 'population-based':ti,ab OR retrospective:ti,ab OR 'pooled
analysis':ti,ab OR crossover:ti,ab OR 'meta-analysis':ti,ab OR 'meta analysis':ti,ab OR prevalence:ti,ab OR risk:ti,ab OR incidence:ti,ab OR
longitudinal:ti,ab OR prospective:ti,ab OR 'risk factors':ti,ab OR 'risk factor':ti,ab OR 'natural history':ti,ab) NOT ('randomized control trial':ti,abOR 'randomized-control trial':ti,ab OR 'randomized control trials':ti,ab OR 'randomized-control trials':ti,ab OR 'randomized controlled
trial':ti,ab OR 'randomized controlled trials':ti,ab OR 'randomized-controlled trial':ti,ab OR 'randomized-controlled trials':ti,ab OR 'randomised
control trial':ti,ab OR 'randomised-control trial':ti,ab OR 'randomised control trials':ti,ab OR 'randomised-control trials':ti,ab OR 'randomised
controlled trial':ti,ab OR 'randomised controlled trials':ti,ab OR 'randomised-controlled trial':ti,ab OR 'randomised-controlled trials':ti,ab OR
rct:ti,ab OR 'randomized trial':ti,ab OR 'randomised trial':ti,ab OR 'randomized control':ti,ab OR 'randomised control':ti,ab OR 'clusterrandomized trial':ti,ab OR 'cluster-randomised trial':ti,ab OR 'randomized double-blind':ti,ab OR 'clinical trial':ti,ab OR 'clinical trials':ti,ab OR'clinical study':ti,ab OR 'clinical studies':ti,ab OR 'clinical conference':ti,ab OR 'clinical conferences':ti,ab OR 'open label':ti,ab OR 'openlabel':ti,ab OR 'phase i':ti,ab OR 'phase 1':ti,ab OR 'phase ii':ti,ab OR 'phase 2':ti,ab OR 'phase iii':ti,ab OR 'phase 3':ti,ab OR autobiography:ti,abOR biography:ti,ab OR 'patient education handout':ti,ab OR webcast:ti,ab) NOT (cell:ti,ab OR 'cell line':ti,ab OR cellular:ti,ab OR tissue:ti,ab OR'in vitro':ti,ab OR 'in vivo':ti,ab OR spectroscopic:ti,ab OR spectrometer:ti,ab OR spectrophotometry:ti,ab OR 'transformation products':ti,abOR 'gene variants':ti,ab OR plant:ti,ab OR pharmacokinetic:ti,ab OR pharmacodynamic:ti,ab OR microscopy:ti,ab OR chromatography:ti,ab OR'mass spectrometry':ti,ab OR 'gene expression':ti,ab) NOT ((animals:ti,ab OR animal:ti,ab OR 'pogona vitticeps':ti,ab OR mice:ti,ab OR
mus:ti,ab OR mouse:ti,ab OR murine:ti,ab OR woodmouse:ti,ab OR rats:ti,ab OR rat:ti,ab OR murinae:ti,ab OR muridae:ti,ab OR cottonrat:ti,abOR cottonrats:ti,ab OR hamster:ti,ab OR hamsters:ti,ab OR cricetinae:ti,ab OR rodentia:ti,ab OR rodent:ti,ab OR rodents:ti,ab OR pigs:ti,ab OR

145

Reference ID: 4675389

pig:ti,ab OR swine:ti,ab OR swines:ti,ab OR piglets:ti,ab OR piglet:ti,ab OR boar:ti,ab OR boars:ti,ab OR 'sus scrofa':ti,ab OR ferrets:ti,ab OR
ferret:ti,ab OR polecat:ti,ab OR polecats:ti,ab OR 'mustela putorius':ti,ab OR 'guinea pigs':ti,ab OR 'guinea pig':ti,ab OR cavia:ti,ab OR
callithrix:ti,ab OR marmoset:ti,ab OR marmosets:ti,ab OR cebuella:ti,ab OR hapale:ti,ab OR octodon:ti,ab OR chinchilla:ti,ab OR
chinchillas:ti,ab OR gerbillinae:ti,ab OR gerbil:ti,ab OR gerbils:ti,ab OR jird:ti,ab OR jirds:ti,ab OR merione:ti,ab OR meriones:ti,ab OR
rabbits:ti,ab OR rabbit:ti,ab OR hares:ti,ab OR hare:ti,ab OR diptera:ti,ab OR flies:ti,ab OR fly:ti,ab OR dipteral:ti,ab OR drosphila:ti,ab OR
drosophilidae:ti,ab OR cats:ti,ab OR cat:ti,ab OR carus:ti,ab OR felis:ti,ab OR nematoda:ti,ab OR nematode:ti,ab OR nematodes:ti,ab OR
sipunculida:ti,ab OR dogs:ti,ab OR dog:ti,ab OR canine:ti,ab OR canines:ti,ab OR canis:ti,ab OR sheep:ti,ab OR sheeps:ti,ab OR mouflon:ti,abOR mouflons:ti,ab OR ovis:ti,ab OR goats:ti,ab OR goat:ti,ab OR capra:ti,ab OR capras:ti,ab OR rupicapra:ti,ab OR chamois:ti,ab OR
haplorhini:ti,ab OR monkey:ti,ab OR monkeys:ti,ab OR anthropoidea:ti,ab OR anthropoids:ti,ab OR saguinus:ti,ab OR tamarin:ti,ab OR
tamarins:ti,ab OR leontopithecus:ti,ab OR hominidae:ti,ab OR ape:ti,ab OR apes:ti,ab OR pan:ti,ab OR paniscus:ti,ab OR 'pan paniscus':ti,ab OR
bonobo:ti,ab OR bonobos:ti,ab OR troglodytes:ti,ab OR 'pan troglodytes':ti,ab OR gibbon:ti,ab OR gibbons:ti,ab OR siamang:ti,ab OR
siamangs:ti,ab OR nomascus:ti,ab OR symphalangus:ti,ab OR chimpanzee:ti,ab OR chimpanzees:ti,ab OR prosimians:ti,ab OR 'bush baby':ti,abOR prosimian:ti,ab OR 'bush babies':ti,ab OR galagos:ti,ab OR galago:ti,ab OR pongidae:ti,ab OR gorilla:ti,ab OR gorillas:ti,ab OR 'pongopygmaeus':ti,ab OR orangutans:ti,ab OR pygmaeus:ti,ab OR lemur:ti,ab OR lemurs:ti,ab OR lemuridae:ti,ab OR horse:ti,ab OR horses:ti,ab OR
pongo:ti,ab OR equus:ti,ab OR cow:ti,ab OR calf:ti,ab OR bull:ti,ab OR chicken:ti,ab OR chickens:ti,ab OR gallus:ti,ab OR quail:ti,ab OR
bird:ti,ab OR birds:ti,ab OR quails:ti,ab OR poultry:ti,ab OR poultries:ti,ab OR fowl:ti,ab OR fowls:ti,ab OR reptile:ti,ab OR reptilia:ti,ab OR
reptiles:ti,ab OR snakes:ti,ab OR snake:ti,ab OR lizard:ti,ab OR lizards:ti,ab OR alligator:ti,ab OR alligators:ti,ab OR crocodile:ti,ab OR
crocodiles:ti,ab OR turtle:ti,ab OR turtles:ti,ab OR amphibian:ti,ab OR amphibians:ti,ab OR amphibia:ti,ab OR frog:ti,ab OR frogs:ti,ab OR
bombina:ti,ab OR salientia:ti,ab OR toad:ti,ab OR toads:ti,ab OR 'epidalea calamita':ti,ab OR salamander:ti,ab OR salamanders:ti,ab OR
eel:ti,ab OR eels:ti,ab OR fish:ti,ab OR fishes:ti,ab OR pisces:ti,ab OR catfish:ti,ab OR catfishes:ti,ab OR siluriformes:ti,ab OR arius:ti,ab OR
heteropneustes:ti,ab OR sheatfish:ti,ab OR perch:ti,ab OR perches:ti,ab OR percidae:ti,ab OR perca:ti,ab OR trout:ti,ab OR trouts:ti,ab OR
char:ti,ab OR chars:ti,ab OR salvelinus:ti,ab OR 'fathead minnow':ti,ab OR minnow:ti,ab OR cyprinidae:ti,ab OR carps:ti,ab OR carp:ti,ab OR
zebrafish:ti,ab OR zebrafishes:ti,ab OR goldfish:ti,ab OR goldfishes:ti,ab OR guppy:ti,ab OR guppies:ti,ab OR chub:ti,ab OR chubs:ti,ab OR
tinca:ti,ab OR barbels:ti,ab OR barbus:ti,ab OR pimephales:ti,ab OR promelas:ti,ab OR 'poecilia reticulata':ti,ab OR mullet:ti,ab OR mullets:ti,abOR seahorse:ti,ab OR seahorses:ti,ab OR 'mugil'/exp OR mugil) AND curema:ti,ab OR 'atlantic cod':ti,ab OR shark:ti,ab OR sharks:ti,ab OR
catshark:ti,ab OR anguilla:ti,ab OR salmonid:ti,ab OR salmonids:ti,ab OR whitefish:ti,ab OR whitefishes:ti,ab OR salmon:ti,ab OR salmons:ti,abOR sole:ti,ab OR solea:ti,ab OR 'sea lamprey':ti,ab OR lamprey:ti,ab OR lampreys:ti,ab OR pumpkinseed:ti,ab OR sunfish:ti,ab OR
sunfishes:ti,ab OR tilapia:ti,ab OR tilapias:ti,ab OR turbot:ti,ab OR turbots:ti,ab OR flatfish:ti,ab OR flatfishes:ti,ab OR sciuridae:ti,ab OR
squirrel:ti,ab OR squirrels:ti,ab OR chipmunk:ti,ab OR chipmunks:ti,ab OR suslik:ti,ab OR susliks:ti,ab OR vole:ti,ab OR voles:ti,ab OR
lemming:ti,ab OR lemmings:ti,ab OR muskrat:ti,ab OR muskrats:ti,ab OR lemmus:ti,ab OR otter:ti,ab OR otters:ti,ab OR marten:ti,ab OR
martens:ti,ab OR martes:ti,ab OR weasel:ti,ab OR badger:ti,ab OR badgers:ti,ab OR ermine:ti,ab OR mink:ti,ab OR sable:ti,ab OR sables:ti,abOR gulo:ti,ab OR gulos:ti,ab OR wolverine:ti,ab OR wolverines:ti,ab OR minks:ti,ab OR mustela:ti,ab OR llama:ti,ab OR llamas:ti,ab OR
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RCT OR “randomized trial” OR “randomised trial” OR “randomized control” OR “randomised control” OR “cluster-randomized trial” OR“cluster-randomised trial” OR “randomized double-blind” OR “clinical trial” OR “clinical trials” OR “clinical study” OR “clinical studies”
OR “clinical conference” OR “clinical conferences” OR “open label” OR “open-label” OR “phase I” OR “phase 1” OR “phase II” OR “phase2” OR “phase III” OR “phase 3” OR autobiography OR biography OR “patient education handout” OR webcast cell OR "cell line" OR
cellular OR tissue OR "in vitro" OR “in vivo” OR spectroscopic OR spectrometer OR spectrophotometry OR "transformation products" OR"gene variants" OR plant OR pharmacokinetic OR pharmacodynamic OR microscopy OR chromatography OR “mass spectrometry” OR“gene expression” animals OR animal OR "Pogona vitticeps" OR mice OR mus OR mouse OR murine OR woodmouse OR rats OR rat OR
murinae OR muridae OR cottonrat OR cottonrats OR hamster OR hamsters OR cricetinae OR rodentia OR rodent OR rodents OR pigs OR pig
OR swine OR swines OR piglets OR piglet OR boar OR boars OR "sus scrofa" OR ferrets OR ferret OR polecat OR polecats OR "mustela
putorius" OR "guinea pigs" OR "guinea pig" OR cavia OR callithrix OR marmoset OR marmosets OR cebuella OR hapale OR octodon OR
chinchilla OR chinchillas OR gerbillinae OR gerbil OR gerbils OR jird OR jirds OR merione OR meriones OR rabbits OR rabbit OR hares
OR hare OR diptera OR flies OR fly OR dipteral OR drosphila OR drosophilidae OR cats OR cat OR carus OR felis OR nematoda OR
nematode OR nematoda OR nematode OR nematodes OR sipunculida OR dogs OR dog OR canine OR canines OR canis OR sheep OR
sheeps OR mouflon OR mouflons OR ovis OR goats OR goat OR capra OR capras OR rupicapra OR chamois OR haplorhini OR monkey OR
monkeys OR anthropoidea OR anthropoids OR saguinus OR tamarin OR tamarins OR leontopithecus OR hominidae OR ape OR apes OR pan
OR paniscus OR "pan paniscus" OR bonobo OR bonobos OR troglodytes OR "pan troglodytes" OR gibbon OR gibbons OR siamang OR
siamangs OR nomascus OR symphalangus OR chimpanzee OR chimpanzees OR prosimians OR "bush baby" OR prosimian OR "bushbabies" OR galagos OR galago OR pongidae OR gorilla OR gorillas OR pongo OR pygmaeus OR "pongo pygmaeus" OR orangutans OR
pygmaeus OR lemur OR lemurs OR lemuridae OR horse OR horses OR pongo OR equus OR cow OR calf OR bull OR chicken OR chickens
OR gallus OR quail OR bird OR birds OR quails OR poultry OR poultries OR fowl OR fowls OR reptile OR reptilia OR reptiles OR snakes
OR snake OR lizard OR lizards OR alligator OR alligators OR crocodile OR crocodiles OR turtle OR turtles OR amphibian OR amphibians
OR amphibia OR frog OR frogs OR bombina OR salientia OR toad OR toads OR "epidalea calamita" OR salamander OR salamanders OR eel
OR eels OR fish OR fishes OR pisces OR catfish OR catfishes OR siluriformes OR arius OR heteropneustes OR sheatfish OR perch OR
perches OR percidae OR perca OR trout OR trouts OR char OR chars OR salvelinus OR "fathead minnow" OR minnow OR cyprinidae OR
carps OR carp OR zebrafish OR zebrafishes OR goldfish OR goldfishes OR guppy OR guppies OR chub OR chubs OR tinca OR barbels OR
barbus OR pimephales OR promelas OR "poecilia reticulata" OR mullet OR mullets OR seahorse OR seahorses OR mugil curema OR"atlantic cod" OR shark OR sharks OR catshark OR anguilla OR salmonid OR salmonids OR whitefish OR whitefishes OR salmon OR
salmons OR sole OR solea OR "sea lamprey" OR lamprey OR lampreys OR pumpkinseed OR sunfish OR sunfishes OR tilapia OR tilapias
OR turbot OR turbots OR flatfish OR flatfishes OR sciuridae OR squirrel OR squirrels OR chipmunk OR chipmunks OR suslik OR susliks
OR vole OR voles OR lemming OR lemmings OR muskrat OR muskrats OR lemmus OR otter OR otters OR marten OR martens OR martes
OR weasel OR badger OR badgers OR ermine OR mink OR minks OR sable OR sables OR gulo OR gulos OR wolverine OR wolverines OR
minks OR mustela OR llama OR llamas OR alpaca OR alpacas OR camelid OR camelids OR guanaco OR guanacos OR chiroptera OR
chiropteras OR bat OR bats OR fox OR foxes OR iguana OR iguanas OR "xenopus laevis" OR parakeet OR parakeets OR parrot OR parrots

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OR donkey OR donkeys OR mule OR mules OR zebra OR zebras OR shrew OR shrews OR bison OR bisons OR buffalo OR buffaloes OR
deer OR deers OR bear OR bears OR panda OR pandas OR "wild hog" OR "wild boar" OR fitchew OR fitch OR beaver OR beavers OR
jerboa OR jerboas OR capybara OR capybaras)))Table E2. Epidemiologic Literature Search #2. Search strings and additional parameters

149

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AND (“social factors”[tw] OR “Social influencing”[tw] OR “social influence”[tw] OR “motivation”[tw] OR“perception”[tw] OR “belief”[tw] OR “social norms”[tw] OR “preference”[tw] OR “social media”[tw] OR “attitude”[tw]OR “behavior”[tw] )NOT (“randomized control trial”[tw] OR “randomized-control trial”[tw] OR “randomized control trials”[tw] OR“randomized-control trials”[tw] OR “randomized controlled trial”[tw] OR “randomized controlled trials”[tw] OR“randomized-controlled trial”[tw] OR “randomized-controlled trials”[tw] OR “randomised control trial”[tw] OR“randomised-control trial”[tw] OR “randomised control trials”[tw] OR “randomised-control trials”[tw] OR “randomised
controlled trial”[tw] OR “randomised controlled trials”[tw] OR “randomised-controlled trial”[tw] OR “randomisedcontrolled trials”[tw] OR RCT[tw] OR “randomized trial”[tw] OR “randomised trial”[tw] OR “randomized control”[tw] OR“randomised control”[tw] OR “cluster-randomized trial”[tw] OR “cluster-randomised trial”[tw] OR “randomized doubleblind”[tw] OR “clinical trial”[tw] OR “clinical trials”[tw] OR “clinical study”[tw] OR “clinical studies”[tw] OR “clinicalconference”[tw] OR “clinical conferences”[tw] OR “open label”[tw] OR “open-label”[tw] OR “phase I”[tw] OR “phase
1”[tw] OR “phase II”[tw] OR “phase 2”[tw] OR “phase III”[tw] OR “phase 3”[tw] OR autobiography[tw] OR biography[tw]OR “patient education handout”[tw] OR webcast[tw])NOT (cell[tw] OR "cell line"[tw] OR cellular[tw] OR tissue[tw] OR "in vitro"[tw] OR “in vivo”[tw] OR spectroscopic[tw] OR
spectrometer[tw] OR spectrophotometry[tw] OR "transformation products"[tw] OR "gene variants"[tw] OR plant[tw]OR pharmacokinetic[tw] OR pharmacodynamic[tw] OR microscopy[tw] OR chromatography[tw] OR “massspectrometry”[tw] OR “gene expression”[tw])NOT (animals[tiab] OR animal[tiab] OR "Pogona vitticeps"[tiab] OR mice[tiab] OR mus[tiab] OR mouse[tiab] ORmurine[tiab] OR woodmouse[tiab] OR rats[tiab] OR rat[tiab] OR murinae[tiab] OR muridae[tiab] OR cottonrat[tiab] OR
cottonrats[tiab] OR hamster[tiab] OR hamsters[tiab] OR cricetinae[tiab] OR rodentia[tiab] OR rodent[tiab] ORrodents[tiab] OR pigs[tiab] OR pig[tiab] OR swine[tiab] OR swines[tiab] OR piglets[tiab] OR piglet[tiab] OR boar[tiab] ORboars[tiab] OR "sus scrofa"[tiab] OR ferrets[tiab] OR ferret[tiab] OR polecat[tiab] OR polecats[tiab] OR "mustela
putorius"[tiab] OR "guinea pigs"[tiab] OR "guinea pig"[tiab] OR cavia[tiab] OR callithrix[tiab] OR marmoset[tiab] ORmarmosets[tiab] OR cebuella[tiab] OR hapale[tiab] OR octodon[tiab] OR chinchilla[tiab] OR chinchillas[tiab] OR
gerbillinae[tiab] OR gerbil[tiab] OR gerbils[tiab] OR jird[tiab] OR jirds[tiab] OR merione[tiab] OR meriones[tiab] OR
rabbits[tiab] OR rabbit[tiab] OR hares[tiab] OR hare[tiab] OR diptera[tiab] OR flies[tiab] OR fly[tiab] OR dipteral[tiab] OR
drosphila[tiab] OR drosophilidae[tiab] OR cats[tiab] OR cat[tiab] OR carus[tiab] OR felis[tiab] OR nematoda[tiab] OR
nematode[tiab] OR nematoda[tiab] OR nematode[tiab] OR nematodes[tiab] OR sipunculida[tiab] OR dogs[tiab] ORdog[tiab] OR canine[tiab] OR canines[tiab] OR canis[tiab] OR sheep[tiab] OR sheeps[tiab] OR mouflon[tiab] OR

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mouflons[tiab] OR ovis[tiab] OR goats[tiab] OR goat[tiab] OR capra[tiab] OR capras[tiab] OR rupicapra[tiab] ORchamois[tiab] OR haplorhini[tiab] OR monkey[tiab] OR monkeys[tiab] OR anthropoidea[tiab] OR anthropoids[tiab] ORsaguinus[tiab] OR tamarin[tiab] OR tamarins[tiab] OR leontopithecus[tiab] OR hominidae[tiab] OR ape[tiab] ORapes[tiab] OR pan[tiab] OR paniscus[tiab] OR "pan paniscus"[tiab] OR bonobo[tiab] OR bonobos[tiab] OR
troglodytes[tiab] OR "pan troglodytes"[tiab] OR gibbon[tiab] OR gibbons[tiab] OR siamang[tiab] OR siamangs[tiab] ORnomascus[tiab] OR symphalangus[tiab] OR chimpanzee[tiab] OR chimpanzees[tiab] OR prosimians[tiab] OR "bushbaby"[tiab] OR prosimian[tiab] OR "bush babies"[tiab] OR galagos[tiab] OR galago[tiab] OR pongidae[tiab] ORgorilla[tiab] OR gorillas[tiab] OR pongo[tiab] OR pygmaeus[tiab] OR "pongo pygmaeus"[tiab] OR orangutans[tiab] ORpygmaeus[tiab] OR lemur[tiab] OR lemurs[tiab] OR lemuridae[tiab] OR horse[tiab] OR horses[tiab] OR pongo[tiab] ORequus[tiab] OR cow[tiab] OR calf[tiab] OR bull[tiab] OR chicken[tiab] OR chickens[tiab] OR gallus[tiab] OR quail[tiab] ORbird[tiab] OR birds[tiab] OR quails[tiab] OR poultry[tiab] OR poultries[tiab] OR fowl[tiab] OR fowls[tiab] OR reptile[tiab]
OR reptilia[tiab] OR reptiles[tiab] OR snakes[tiab] OR snake[tiab] OR lizard[tiab] OR lizards[tiab] OR alligator[tiab] ORalligators[tiab] OR crocodile[tiab] OR crocodiles[tiab] OR turtle[tiab] OR turtles[tiab] OR amphibian[tiab] OR
amphibians[tiab] OR amphibia[tiab] OR frog[tiab] OR frogs[tiab] OR bombina[tiab] OR salientia[tiab] OR toad[tiab] ORtoads[tiab] OR "epidalea calamita"[tiab] OR salamander[tiab] OR salamanders[tiab] OR eel[tiab] OR eels[tiab] ORfish[tiab] OR fishes[tiab] OR pisces[tiab] OR catfish[tiab] OR catfishes[tiab] OR siluriformes[tiab] OR arius[tiab] ORheteropneustes[tiab] OR sheatfish[tiab] OR perch[tiab] OR perches[tiab] OR percidae[tiab] OR perca[tiab] OR trout[tiab]
OR trouts[tiab] OR char[tiab] OR chars[tiab] OR salvelinus[tiab] OR "fathead minnow"[tiab] OR minnow[tiab] OR
cyprinidae[tiab] OR carps[tiab] OR carp[tiab] OR zebrafish[tiab] OR zebrafishes[tiab] OR goldfish[tiab] OR
goldfishes[tiab] OR guppy[tiab] OR guppies[tiab] OR chub[tiab] OR chubs[tiab] OR tinca[tiab] OR barbels[tiab] OR
barbus[tiab] OR pimephales[tiab] OR promelas[tiab] OR "poecilia reticulata"[tiab] OR mullet[tiab] OR mullets[tiab] ORseahorse[tiab] OR seahorses[tiab] OR mugil curema[tiab] OR "atlantic cod"[tiab] OR shark[tiab] OR sharks[tiab] ORcatshark[tiab] OR anguilla[tiab] OR salmonid[tiab] OR salmonids[tiab] OR whitefish[tiab] OR whitefishes[tiab] ORsalmon[tiab] OR salmons[tiab] OR sole[tiab] OR solea[tiab] OR "sea lamprey"[tiab] OR lamprey[tiab] OR lampreys[tiab]
OR pumpkinseed[tiab] OR sunfish[tiab] OR sunfishes[tiab] OR tilapia[tiab] OR tilapias[tiab] OR turbot[tiab] ORturbots[tiab] OR flatfish[tiab] OR flatfishes[tiab] OR sciuridae[tiab] OR squirrel[tiab] OR squirrels[tiab] ORchipmunk[tiab] OR chipmunks[tiab] OR suslik[tiab] OR susliks[tiab] OR vole[tiab] OR voles[tiab] OR lemming[tiab] ORlemmings[tiab] OR muskrat[tiab] OR muskrats[tiab] OR lemmus[tiab] OR otter[tiab] OR otters[tiab] OR marten[tiab] ORmartens[tiab] OR martes[tiab] OR weasel[tiab] OR badger[tiab] OR badgers[tiab] OR ermine[tiab] OR mink[tiab] ORminks[tiab] OR sable[tiab] OR sables[tiab] OR gulo[tiab] OR gulos[tiab] OR wolverine[tiab] OR wolverines[tiab] ORminks[tiab] OR mustela[tiab] OR llama[tiab] OR llamas[tiab] OR alpaca[tiab] OR alpacas[tiab] OR camelid[tiab] ORcamelids[tiab] OR guanaco[tiab] OR guanacos[tiab] OR chiroptera[tiab] OR chiropteras[tiab] OR bat[tiab] OR bats[tiab]
152

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‘survey’:ti,ab OR ‘questionnaire’:ti,ab OR ‘web scrapping’:ti,ab OR ‘cryptomarket’:ti,ab OR ‘darknet’:ti,ab OR ‘digital
trace’:ti,ab OR ‘AlphaBay’:ti,ab OR ‘Valhalla’:ti,ab OR ‘Tor Network’:ti,ab OR ‘market data’:ti,ab OR ‘social media’:ti,abOR ‘social environment’:ti,ab) AND (‘social factors’:ti,ab OR ‘Social influencing’:ti,ab OR ‘social influence’:ti,ab OR‘motivation’:ti,ab OR ‘perception’:ti,ab OR ‘belief’:ti,ab OR ‘social norms’:ti,ab OR ‘preference’:ti,ab OR ‘social
media’:ti,ab OR ‘attitude’:ti,ab OR ‘behavior’:ti,ab)
NOT ('randomized control trial':ti,ab OR 'randomized-control trial':ti,ab OR 'randomized control trials':ti,ab OR'randomized-control trials':ti,ab OR 'randomized controlled trial':ti,ab OR 'randomized controlled trials':ti,ab OR'randomized-controlled trial':ti,ab OR 'randomized-controlled trials':ti,ab OR 'randomised control trial':ti,ab OR'randomised-control trial':ti,ab OR 'randomised control trials':ti,ab OR 'randomised-control trials':ti,ab OR 'randomised
controlled trial':ti,ab OR 'randomised controlled trials':ti,ab OR 'randomised-controlled trial':ti,ab OR 'randomisedcontrolled trials':ti,ab OR rct:ti,ab OR 'randomized trial':ti,ab OR 'randomised trial':ti,ab OR 'randomized control':ti,abOR 'randomised control':ti,ab OR 'cluster-randomized trial':ti,ab OR 'cluster-randomised trial':ti,ab OR 'randomized
double-blind':ti,ab OR 'clinical trial':ti,ab OR 'clinical trials':ti,ab OR 'clinical study':ti,ab OR 'clinical studies':ti,ab OR'clinical conference':ti,ab OR 'clinical conferences':ti,ab OR 'open label':ti,ab OR 'open-label':ti,ab OR 'phase i':ti,ab OR'phase 1':ti,ab OR 'phase ii':ti,ab OR 'phase 2':ti,ab OR 'phase iii':ti,ab OR 'phase 3':ti,ab OR autobiography:ti,ab OR
biography:ti,ab OR 'patient education handout':ti,ab OR webcast:ti,ab) NOT (cell:ti,ab OR 'cell line':ti,ab OR cellular:ti,abOR tissue:ti,ab OR 'in vitro':ti,ab OR 'in vivo':ti,ab OR spectroscopic:ti,ab OR spectrometer:ti,ab OR
spectrophotometry:ti,ab OR 'transformation products':ti,ab OR 'gene variants':ti,ab OR plant:ti,ab OR
pharmacokinetic:ti,ab OR pharmacodynamic:ti,ab OR microscopy:ti,ab OR chromatography:ti,ab OR 'mass
spectrometry':ti,ab OR 'gene expression':ti,ab) NOT ((animals:ti,ab OR animal:ti,ab OR 'pogona vitticeps':ti,ab OR
mice:ti,ab OR mus:ti,ab OR mouse:ti,ab OR murine:ti,ab OR woodmouse:ti,ab OR rats:ti,ab OR rat:ti,ab OR murinae:ti,abOR muridae:ti,ab OR cottonrat:ti,ab OR cottonrats:ti,ab OR hamster:ti,ab OR hamsters:ti,ab OR cricetinae:ti,ab OR
rodentia:ti,ab OR rodent:ti,ab OR rodents:ti,ab OR pigs:ti,ab OR pig:ti,ab OR swine:ti,ab OR swines:ti,ab OR piglets:ti,abOR piglet:ti,ab OR boar:ti,ab OR boars:ti,ab OR 'sus scrofa':ti,ab OR ferrets:ti,ab OR ferret:ti,ab OR polecat:ti,ab OR
polecats:ti,ab OR 'mustela putorius':ti,ab OR 'guinea pigs':ti,ab OR 'guinea pig':ti,ab OR cavia:ti,ab OR callithrix:ti,ab OR
marmoset:ti,ab OR marmosets:ti,ab OR cebuella:ti,ab OR hapale:ti,ab OR octodon:ti,ab OR chinchilla:ti,ab OR
chinchillas:ti,ab OR gerbillinae:ti,ab OR gerbil:ti,ab OR gerbils:ti,ab OR jird:ti,ab OR jirds:ti,ab OR merione:ti,ab OR
meriones:ti,ab OR rabbits:ti,ab OR rabbit:ti,ab OR hares:ti,ab OR hare:ti,ab OR diptera:ti,ab OR flies:ti,ab OR fly:ti,ab OR
dipteral:ti,ab OR drosphila:ti,ab OR drosophilidae:ti,ab OR cats:ti,ab OR cat:ti,ab OR carus:ti,ab OR felis:ti,ab OR
nematoda:ti,ab OR nematode:ti,ab OR nematodes:ti,ab OR sipunculida:ti,ab OR dogs:ti,ab OR dog:ti,ab OR canine:ti,abOR canines:ti,ab OR canis:ti,ab OR sheep:ti,ab OR sheeps:ti,ab OR mouflon:ti,ab OR mouflons:ti,ab OR ovis:ti,ab OR

154

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goats:ti,ab OR goat:ti,ab OR capra:ti,ab OR capras:ti,ab OR rupicapra:ti,ab OR chamois:ti,ab OR haplorhini:ti,ab ORmonkey:ti,ab OR monkeys:ti,ab OR anthropoidea:ti,ab OR anthropoids:ti,ab OR saguinus:ti,ab OR tamarin:ti,ab OR
tamarins:ti,ab OR leontopithecus:ti,ab OR hominidae:ti,ab OR ape:ti,ab OR apes:ti,ab OR pan:ti,ab OR paniscus:ti,ab OR'pan paniscus':ti,ab OR bonobo:ti,ab OR bonobos:ti,ab OR troglodytes:ti,ab OR 'pan troglodytes':ti,ab OR gibbon:ti,abOR gibbons:ti,ab OR siamang:ti,ab OR siamangs:ti,ab OR nomascus:ti,ab OR symphalangus:ti,ab OR chimpanzee:ti,ab OR
chimpanzees:ti,ab OR prosimians:ti,ab OR 'bush baby':ti,ab OR prosimian:ti,ab OR 'bush babies':ti,ab OR galagos:ti,abOR galago:ti,ab OR pongidae:ti,ab OR gorilla:ti,ab OR gorillas:ti,ab OR 'pongo pygmaeus':ti,ab OR orangutans:ti,ab OR
pygmaeus:ti,ab OR lemur:ti,ab OR lemurs:ti,ab OR lemuridae:ti,ab OR horse:ti,ab OR horses:ti,ab OR pongo:ti,ab OR
equus:ti,ab OR cow:ti,ab OR calf:ti,ab OR bull:ti,ab OR chicken:ti,ab OR chickens:ti,ab OR gallus:ti,ab OR quail:ti,ab OR
bird:ti,ab OR birds:ti,ab OR quails:ti,ab OR poultry:ti,ab OR poultries:ti,ab OR fowl:ti,ab OR fowls:ti,ab OR reptile:ti,ab
OR reptilia:ti,ab OR reptiles:ti,ab OR snakes:ti,ab OR snake:ti,ab OR lizard:ti,ab OR lizards:ti,ab OR alligator:ti,ab OR
alligators:ti,ab OR crocodile:ti,ab OR crocodiles:ti,ab OR turtle:ti,ab OR turtles:ti,ab OR amphibian:ti,ab OR
amphibians:ti,ab OR amphibia:ti,ab OR frog:ti,ab OR frogs:ti,ab OR bombina:ti,ab OR salientia:ti,ab OR toad:ti,ab OR
toads:ti,ab OR 'epidalea calamita':ti,ab OR salamander:ti,ab OR salamanders:ti,ab OR eel:ti,ab OR eels:ti,ab OR fish:ti,abOR fishes:ti,ab OR pisces:ti,ab OR catfish:ti,ab OR catfishes:ti,ab OR siluriformes:ti,ab OR arius:ti,ab OR
heteropneustes:ti,ab OR sheatfish:ti,ab OR perch:ti,ab OR perches:ti,ab OR percidae:ti,ab OR perca:ti,ab OR trout:ti,ab
OR trouts:ti,ab OR char:ti,ab OR chars:ti,ab OR salvelinus:ti,ab OR 'fathead minnow':ti,ab OR minnow:ti,ab OR
cyprinidae:ti,ab OR carps:ti,ab OR carp:ti,ab OR zebrafish:ti,ab OR zebrafishes:ti,ab OR goldfish:ti,ab OR goldfishes:ti,abOR guppy:ti,ab OR guppies:ti,ab OR chub:ti,ab OR chubs:ti,ab OR tinca:ti,ab OR barbels:ti,ab OR barbus:ti,ab OR
pimephales:ti,ab OR promelas:ti,ab OR 'poecilia reticulata':ti,ab OR mullet:ti,ab OR mullets:ti,ab OR seahorse:ti,ab OR
seahorses:ti,ab OR 'mugil'/exp OR mugil) AND curema:ti,ab OR 'atlantic cod':ti,ab OR shark:ti,ab OR sharks:ti,ab OR
catshark:ti,ab OR anguilla:ti,ab OR salmonid:ti,ab OR salmonids:ti,ab OR whitefish:ti,ab OR whitefishes:ti,ab OR
salmon:ti,ab OR salmons:ti,ab OR sole:ti,ab OR solea:ti,ab OR 'sea lamprey':ti,ab OR lamprey:ti,ab OR lampreys:ti,ab OR
pumpkinseed:ti,ab OR sunfish:ti,ab OR sunfishes:ti,ab OR tilapia:ti,ab OR tilapias:ti,ab OR turbot:ti,ab OR turbots:ti,abOR flatfish:ti,ab OR flatfishes:ti,ab OR sciuridae:ti,ab OR squirrel:ti,ab OR squirrels:ti,ab OR chipmunk:ti,ab OR
chipmunks:ti,ab OR suslik:ti,ab OR susliks:ti,ab OR vole:ti,ab OR voles:ti,ab OR lemming:ti,ab OR lemmings:ti,ab OR
muskrat:ti,ab OR muskrats:ti,ab OR lemmus:ti,ab OR otter:ti,ab OR otters:ti,ab OR marten:ti,ab OR martens:ti,ab OR
martes:ti,ab OR weasel:ti,ab OR badger:ti,ab OR badgers:ti,ab OR ermine:ti,ab OR mink:ti,ab OR sable:ti,ab OR
sables:ti,ab OR gulo:ti,ab OR gulos:ti,ab OR wolverine:ti,ab OR wolverines:ti,ab OR minks:ti,ab OR mustela:ti,ab OR
llama:ti,ab OR llamas:ti,ab OR alpaca:ti,ab OR alpacas:ti,ab OR camelid:ti,ab OR camelids:ti,ab OR guanaco:ti,ab OR
guanacos:ti,ab OR chiroptera:ti,ab OR chiropteras:ti,ab OR bat:ti,ab OR bats:ti,ab OR fox:ti,ab OR foxes:ti,ab OR
iguana:ti,ab OR iguanas:ti,ab OR 'xenopus laevis':ti,ab OR parakeet:ti,ab OR parakeets:ti,ab OR parrot:ti,ab OR
155

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OR “randomized-control trial” OR “randomized control trials” OR “randomized-control trials” OR “randomized
controlled trial” OR “randomized controlled trials” OR “randomized-controlled trial” OR “randomized-controlled trials”
OR “randomised control trial” OR “randomised-control trial” OR “randomised control trials” OR “randomised-control
trials” OR “randomised controlled trial” OR “randomised controlled trials” OR “randomised-controlled trial” OR“randomised-controlled trials” OR RCT OR “randomized trial” OR “randomised trial” OR “randomized control” OR“randomised control” OR “cluster-randomized trial” OR “cluster-randomised trial” OR “randomized double-blind” OR“clinical trial” OR “clinical trials” OR “clinical study” OR “clinical studies” OR “clinical conference” OR “clinicalconferences” OR “open label” OR “open-label” OR “phase I” OR “phase 1” OR “phase II” OR “phase 2” OR “phase III” OR“phase 3” OR autobiography OR biography OR “patient education handout” OR webcast cell OR "cell line" OR cellular
OR tissue OR "in vitro" OR “in vivo” OR spectroscopic OR spectrometer OR spectrophotometry OR "transformation
products" OR "gene variants" OR plant OR pharmacokinetic OR pharmacodynamic OR microscopy OR chromatography
OR “mass spectrometry” OR “gene expression” animals OR animal OR "Pogona vitticeps" OR mice OR mus OR mouse OR
murine OR woodmouse OR rats OR rat OR murinae OR muridae OR cottonrat OR cottonrats OR hamster OR hamsters
OR cricetinae OR rodentia OR rodent OR rodents OR pigs OR pig OR swine OR swines OR piglets OR piglet OR boar OR
boars OR "sus scrofa" OR ferrets OR ferret OR polecat OR polecats OR "mustela putorius" OR "guinea pigs" OR "guinea
pig" OR cavia OR callithrix OR marmoset OR marmosets OR cebuella OR hapale OR octodon OR chinchilla OR chinchillas
OR gerbillinae OR gerbil OR gerbils OR jird OR jirds OR merione OR meriones OR rabbits OR rabbit OR hares OR hare OR
diptera OR flies OR fly OR dipteral OR drosphila OR drosophilidae OR cats OR cat OR carus OR felis OR nematoda OR
nematode OR nematoda OR nematode OR nematodes OR sipunculida OR dogs OR dog OR canine OR canines OR canis
OR sheep OR sheeps OR mouflon OR mouflons OR ovis OR goats OR goat OR capra OR capras OR rupicapra OR chamois
OR haplorhini OR monkey OR monkeys OR anthropoidea OR anthropoids OR saguinus OR tamarin OR tamarins OR
leontopithecus OR hominidae OR ape OR apes OR pan OR paniscus OR "pan paniscus" OR bonobo OR bonobos OR
troglodytes OR "pan troglodytes" OR gibbon OR gibbons OR siamang OR siamangs OR nomascus OR symphalangus OR
chimpanzee OR chimpanzees OR prosimians OR "bush baby" OR prosimian OR "bush babies" OR galagos OR galago OR
pongidae OR gorilla OR gorillas OR pongo OR pygmaeus OR "pongo pygmaeus" OR orangutans OR pygmaeus OR lemur
OR lemurs OR lemuridae OR horse OR horses OR pongo OR equus OR cow OR calf OR bull OR chicken OR chickens OR
gallus OR quail OR bird OR birds OR quails OR poultry OR poultries OR fowl OR fowls OR reptile OR reptilia OR reptiles
OR snakes OR snake OR lizard OR lizards OR alligator OR alligators OR crocodile OR crocodiles OR turtle OR turtles OR
amphibian OR amphibians OR amphibia OR frog OR frogs OR bombina OR salientia OR toad OR toads OR "epidalea
calamita" OR salamander OR salamanders OR eel OR eels OR fish OR fishes OR pisces OR catfish OR catfishes OR
siluriformes OR arius OR heteropneustes OR sheatfish OR perch OR perches OR percidae OR perca OR trout OR trouts
OR char OR chars OR salvelinus OR "fathead minnow" OR minnow OR cyprinidae OR carps OR carp OR zebrafish OR
157

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zebrafishes OR goldfish OR goldfishes OR guppy OR guppies OR chub OR chubs OR tinca OR barbels OR barbus OR
pimephales OR promelas OR "poecilia reticulata" OR mullet OR mullets OR seahorse OR seahorses OR mugil curema OR"atlantic cod" OR shark OR sharks OR catshark OR anguilla OR salmonid OR salmonids OR whitefish OR whitefishes OR
salmon OR salmons OR sole OR solea OR "sea lamprey" OR lamprey OR lampreys OR pumpkinseed OR sunfish OR
sunfishes OR tilapia OR tilapias OR turbot OR turbots OR flatfish OR flatfishes OR sciuridae OR squirrel OR squirrels OR
chipmunk OR chipmunks OR suslik OR susliks OR vole OR voles OR lemming OR lemmings OR muskrat OR muskrats OR
lemmus OR otter OR otters OR marten OR martens OR martes OR weasel OR badger OR badgers OR ermine OR mink OR
minks OR sable OR sables OR gulo OR gulos OR wolverine OR wolverines OR minks OR mustela OR llama OR llamas OR
alpaca OR alpacas OR camelid OR camelids OR guanaco OR guanacos OR chiroptera OR chiropteras OR bat OR bats OR
fox OR foxes OR iguana OR iguanas OR "xenopus laevis" OR parakeet OR parakeets OR parrot OR parrots OR donkey OR
donkeys OR mule OR mules OR zebra OR zebras OR shrew OR shrews OR bison OR bisons OR buffalo OR buffaloes OR
deer OR deers OR bear OR bears OR panda OR pandas OR "wild hog" OR "wild boar" OR fitchew OR fitch OR beaver OR
beavers OR jerboa OR jerboas OR capybara OR capybaras)))158

Reference ID: 4675389

APPENDIX F. LITERATURE REVIEW ABSTRACTION

Table F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source

Study Design(include years)

Population

Exposure

Outcomes

Notable findings

Comments

Airagnes, 2019

Nationalprescription drug
benefitadministrative
database (20092015), self-reportquestionnaire forsocial anddemographic
information

Population-based
cross-sectional
study(CONSTANCES
cohort)Random sample
of French
population(covered bygeneral healthinsurance
scheme), aged
18–69 years in
2015; 4,686 men
and 4,849 womenSociodemographic
variables: age,gender,occupational status,
occupational grade,household income,marital status,
education level,
depressive
symptoms(depressive state
was defined as a
total score > 18 at
the Center for
EpidemiologicalStudies Depression
Scale), at-risk
alcohol use

Long-term
benzodiazepine
use: a continuous
period ofprescription
benzodiazepine
longer than 12
weeks (binary
variable i.e.,presence vsabsence): 1) At
least two refills
in the 12 weeks
following thefirst prescription
and 2) at least
one refill in week
13–14 or at least
one refill in week
15–16 if the lastrefill observed
during the first
12 weeks occurs
on week 11–12.
Assessed as
cross-sectional
data

Weighted analyses toprovide representative
results of the French
general population.
Weighted prevalence ofbenzodiazepine long-term
use during 2009-2015:
2.8% (95% CI:2.3–3.4)
for men and 3.8% (95%
CI: 3.3–4.5) for women.
Individual models foreach factor stratified bysex. Factors positively
associated withbenzodiazepine long-term
use, adjusted for sex:
increased age, low
education, not being atwork, low occupational
grade, low income, notbeing in a couple anddepressive symptoms.

Cross-sectional
data precluded
assessment of
temporality, e.g.,
for the association
with depressive
symptoms. Crosssectional
associations werestratified by sex
with no further
adjustment.
Although over
90% of the French
population was
eligible for the
sample, people
were not eligible ifthey were selfemployed or
agricultural
workers.

a159

Reference ID: 4675389

Table F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source

Study Design(include years)

Population

Exposure

Outcomes

Notable findings

Comments

de las Cuevas,
2003 bSeverity
Dependence Scale(SDS) and Healthrecords

Cross-sectional
study; Jan toApril 2002

Inclusion criteria:
Consecutive
patients(N=1,048)
attending primarycare healthcenters in the
Canary Islands
Health Service,currently on
benzodiazepine
treatment for 1
month or longer(mean 38.2+/-52
months, range 1–
360 months). Age
18-80 years old
and a stable
maintenancedosage of theirbenzodiazepine at
the time of thestudy entry in therange of 2.5–50
mg/day ofdiazepam or its
equivalent.
Exclusion
criteria: current
diagnosis of
schizophrenia ororganic brain
syndrome,
alcoholism orPatient factors:
gender, age, marital
status, education,
employment.

Benzodiazepine
dependence,using the severityof dependence
scale (SDS)
which is a short
is a 5-item, selfreportquestionnaire.
cross-sectional
measurementwith exposures

47% of patients using
benzodiazepines for morethan 1 month reported
dependence.
Benzodiazepine
dependence was moreprevalent among women,
middle aged. In logistic
regression model
adjusting for dosage,
duration andantidepressant use, theprobability of developing
benzodiazepine
dependence wasassociated with the
benzodiazepine dose used
(1.04; 95% CI 1.03, 1.06),
the duration of this use(1.01; 95% CI 1.009,
1.02)) and suggestively
with the concomitant useof antidepressants (0.681;(95% CI: 0.45, 1.03).
Concomitant use ofantidepressants was
positively associated withdependence before
adjusting for dose andduration.

Strengths:
relatively large
sample size; wide
range of age (1880); included
sociodemographic
information;

Characteristics ofbenzodiazepine use:
dose, duration of
use.

160

Reference ID: 4675389

Limitations:-cross-sectional
measurement of
exposure andoutcomes
precluded
assessment of
causality;-unclear why only
three variables
were included in
the multivariableadjusted model.

Table F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source

Study Design(include years)

Population

Exposure

Outcomes

Notable findings

Comments

Clinical diagnoses
coded prior to or
concurrent withinitialbenzodiazepine
prescription (using
ICD-9 codes) of
PTSD, alcohol
dependence andabuse, alcoholism
related medical andpsychiatricdiagnoses,
psychoactive drug
dependence, drug
abuse and
withdrawal
syndromes.

High-dose(defined as
patients whose
average daily
dose for theirlongest treatment
episode was in
the top 10% foreach agent)anxiolytic
benzodiazepine
prescriptions

Using descriptive
analyses, they found drug
abuse diagnosis associatedwith high-dose
benzodiazepines.
Multivariable logistic
regression (adjusted forsex, age, year treatment
started, treatment
duration, drug abuse andconcurrent
acetaminophen/oxycodone prescription)
among patients with
PTSD and alcoholism
diagnoses receiving longterm, found that risks forhigh-dose
benzodiazepines werehigher in younger ages
(OR 2.98 95% CI 1.306.84), having 12-26

Strengths:
Longitudinal study
design with long
follow-up andlarge sample size
(n=3,612 with new
benzodiazepine
prescription and
PTSD diagnosis).

substance abuse(past 12 months).
Acute or unstable
medical or
psychiatriccondition, unable
to completequestionnaire.

Hermos,2007 dPharmacy andmedical claims
databases from theVeterans
Administration,
New England
Veterans Integrated
Service Network

Retrospective
population-based
study; 19972003 (six-year
follow-up
window)

Veteran patientsin the eight
distinct New
England VA
Medical Centers
and affiliatedclinics in New
England Veterans
Integrated Service
Network;
Inclusion criteria:
patients with newprescriptions foralprazolam,clonazepam,
diazepam, or
lorazepam;
treatment
episodes defined
as long-term use,i.e., threebenzodiazepine

161

Reference ID: 4675389

Limitations: VA
data may have
limitedinformation on
medical diagnoses;
lack ofgeneralizability:
VA population
with PTSD; Olderdata; unclear why
logistic regression
was used insteadTable F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source

Study Design(include years)

Population

Exposure

Outcomesprescriptions
filled within 120day period; and at
least 2 diagnosisof posttraumaticstress disorder(PTSD) prior to
or concurrent
with newbenzodiazepine
prescription

Luijendijk,
2008 eInterview(including
instruments fordepressive
symptoms, anxiety,cognitive function,and self-rated
health) andprescription drug
dispensing data

Prospective
cohort study
Baseline datacollection: July
1993 toDecember 1995.
Participants
followed until
event (chronic
benzodiazepineuse), death, lossto-follow-up, or
end of study(January 1,
2003)

Elderly (ages 55
and older atbaseline)
residents ofRotterdam, theNetherlands,
n=5364
Exclusion
criteria:
Participants who
had chronic
benzodiazepineuse (see outcome)in the 2 years
before baseline

Three domains ofpotential predictors:social support,
psychiatric andsomatic health,participant's healthperception andbehavior

162

Reference ID: 4675389

Chronic
benzodiazepine
use: at least 180
days ofcontinuous orintermittent use
during aconsecutive
period of 365
days
assessed among
two populations:
1. general
population(n=5364) and 2.
subset that filled
at least one
benzodiazepine
prescription(n=2490)

Notable findings

Comments

months duration oftreatment (OR 2.54 95%
CI: 1.33-4.86), drug abuse
diagnoses (OR 1.80 95%
CI 1.06-3.08), concurrent
benzodiazepine (OR 5.55
95% CI 2.31-13.33) andconcurrent
acetaminophen/oxycodone(OR 2.43 95% CI 1.224.83)

of cox proportional
hazard models.

Average follow-up: 7.3
years
440 new chronic
benzodiazepine users
among 39,164 personyears.
2,490 participants filled atleast one prescription for
benzodiazepine and17.7% became chronicusers
Cox proportional hazard
analyses, multivariable(HR (95% CI)):

Strengths:
longitudinal study
design; assessed
depressive
symptoms andanxiety via inperson instrument
Limitations:
Underlying
physical andmental healthstatus may haveconfounded theinverse association
between living
alone and chronic
BZD use; anxiety
information was
limited (onlyinformation on

Predictors for new-onset
chronic benzodiazepine
use in those who had
filled at least one
prescription: increasing

Also, unclear why
multivariable
analysis was
conducted in a sub
population ofpatients diagnosed
with PTSD andalcoholism
receiving longterm
benzodiazepines.

Table F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Manthey,
2012 f

Data Source

self-reportquestionnaires,
telephone and inperson interviews,
medicalexamination

Study Design(include years)

Cross-sectional
study

Population

Subjects (n=401)
recruited from
community as
well as generalpractice andmental healthcare institutions;
Were part of alarger sample
designed to be
representative of
individuals ages
18-64 years withdepressive and/or
anxiety disorders
in theNetherlands.
Inclusion criteria:benzodiazepine
use in the monthprior to interview,completion of the
Bendep-SRQ,
screen positive
for affective or
anxiety disorders.

Exposure

Domains forpotential correlatesof benzodiazepine
dependence: (i)socio-demographic
factors, (ii)psychologicalfactors, (iii) physicalfactors, (iv)addiction-related
factors and (v)factors related to theuse of BZDs

163

Reference ID: 4675389

Outcomes

Dependence
measured on the
Bendep-SRQ in
three domains: (i)awareness ofproblematic use,(ii)
preoccupation
with theavailability ofbenzodiazepinesand (iii) lack ofcompliance withthe therapeutic
regimen

Notable findings

Commentsage (1.04 (1.03, 1.06)),
public health insurance(1.24 (1.01, 1.51)) andpain related joint
complaints predicted (1.32(1.06, 1.64)); living alone
was protective (0.73 (0.58,0.93)).

subset of
population); notclear how all
variables wereassessed in theinterview

Analyses: descriptive andmultivariable linear
regression.
Median duration of
benzodiazepine use was
24 months (interquartile
range: 5-96) and theaverage daily dose was
2.8-mg diazepam
equivalents per day
Factors that displayedcross-sectional correlation
with domains ofdependence score in
multivariable linear
regression are listed
below. Coefficients are
difficult to interpret andare therefore not reported
here. Problematic use:
more GP contacts in thepast 6 months, severity of
insomnia andantidepressant use.
Consistent results among
subset of participants with

Strengths:
Assessedbenzodiazepine
dependence using
a validated
instrument tocollect patientreported
information, rather
than relying onprescription
dispensing data.
Limitations:
Cross-sectional
study design could
examine factors
correlated withBZD dependence;
impossible toassess theirrespective
contribution todependence.
Results were
presented as betacoefficients only

Table F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source

Study Design(include years)

Population

Exposure

164

Reference ID: 4675389

Outcomes

Notable findings

Comments

frequent benzodiazepine
use but antidepressant use
was less associated.
Positively associated withpreoccupation withavailability ofbenzodiazepines(multivariable linear
regression): higher scoreson the Beck Anxiety
Inventory, antidepressantuse, alcohol dependence
and a higher daily dosageof BZDs. Alcohol
dependence and anxiety
remained significant
among subset ofparticipants with frequentbenzodiazepine use.
Associated with lack ofcompliance: older age,
unemployment due tosickness or disability,
more severe insomnia,
antidepressant use andalcohol dependence.
Unemployment, insomnia
and alcohol dependence,
and antidepressant use
remained stable among
subset of participants withfrequent benzodiazepineuse.
Insomnia, antidepressantwith limited
interpretation
provided byauthors

Table F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source

Study Design(include years)

Population

Exposure

Outcomes

Notable findings

Comments

use and alcohol
dependence may increase
the risk of benzodiazepine
dependence amongindividuals who use
benzodiazepines.

Mol, 2005 g

32-itemBenzodiazepine
Craving
Questionnaire(BCQ) andmultiple self-reportquestionnaires:information on
lifestyle,dependence
characteristics,
personality traits(Dutch shortened
MMPI (NVM),
short-termchangeable moodstates (Dutch
shortened Profile
of Mood States(POMS),
psychopathology

Cross-sectionaland only
included
information fromthe
Benzodiazepine
Craving
Questionnairecompleted atbaseline of larger
study focusing
long-term
benzodiazepine
use in generalpractice. Study
years: August
1998 and
December 2001.

Netherlands;
General practicepatients who
recently
discontinued theirlong-term
benzodiazepine orfailed to do so(n=113 long-termand 80 former
long-term patientsusing
benzodiazepines);
long-term use
defined as use formore than 3months;benzodiazepine
craving from BCQ

Exclusion
criteria: current
psychiatric

165

Reference ID: 4675389

Domains ofpotential
predictors forbenzodiazepine
craving:benzodiazepine
dependence
severity,
psychopathology,
mood state,
personality, andlifestyleStatistical comparison
between patients reporting
benzodiazepine cravingsand patients not reporting
benzodiazepine cravings.
Bivariate and multivariate
logistic regression withcraving (yes/no) as
dependent variable.
Craving was reported by
22.5% (18/80) of thepatients who had
discontinued their use vs40.7% (46/113) of those
who had not.
Eight factors (anger,
depression, mental health,role functioning, social
functioning, somatization,negativism, score on
GHQ-12) were associatedPatients reporting
cravings differedfrom patients notreporting cravingin the following
domains:benzodiazepine
dependence,
psychopathology,
negative moodstate, andpersonality
Strengths: Directly
assessed a patientreported measureof benzodiazepine
dependence and its
cross-sectionalcorrelation withmeasures of moodTable F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source(General Health
Questionnaire 12item), healthrelated quality oflife (Medical
Outcome Study
Short-Form 36item)

Study Design(include years)

Population

Exposuretreatment, current
treatment for drugor alcohol
dependence,
medical history ofpsychosis,
epilepsy or
terminal illness
and inability tocommunicate in
Dutch language.

a

Outcomes

Notable findings

Comments

with craving after
adjusting for current use
status (no other factors inmodel).
Results frommultivariable-adjusted
models: no factors otherthan depression andsomatization, which werehighly correlated,remained significant.

andpsychopathology
among patientswith current or
past long-term
BZD use.
Limitations:
Cross-sectional
study. Adjustingfor current use
status in the
regression model
make thecorrelationsdifficult tointerpret – would
have been morestraightforward topresent results
stratified bycurrent use status.

Airagnes, G., Lemogne, C., Renuy, A., Goldberg, M., Hoertel, N., Roquelaure, Y., Zins, M. (2019). Prevalence of prescribed benzodiazepine long-term use
in the French general population according to sociodemographic and clinical factors: findings from the CONSTANCES cohort. Bmc Public Health.
bde las Cuevas, C., San, E., & de la Fuente, J. (2003). Benzodiazepines: more "behavioural" addiction than dependence. Psychopharmacology (Berl), 297303.
c
Fride Tvete, I., Bjørner, T., & Skomedal, T. (2015). Risk factors for excessive benzodiazepine use in a working age population: a nationwide 5-year survey
in Norway. Scandinavian journal of primary health care, 252-259.
dHermos, J. A., Young, M. M., Lawler, E. V., Rosenbloom, D., & Fiore, L. D. (2007). Long-term, high-dose benzodiazepine prescriptions in veteran patientswith PTSD: influence of preexisting alcoholism and drug-abuse diagnoses. J Trauma Stress, 909-14.
eLuijendijk, H. J., Tiemeier, H., Hofman, A., Heeringa, J., & Stricker, B. H. (2008). Determinants of chronic benzodiazepine use in the elderly: a longitudinal
study. British Journal of Clinical Pharmacology, 65, 593-599.

166

Reference ID: 4675389

Table F1. Articles included Literature Review: Risks (Dependence, Misuse, Abuse, Addiction) Associated with Long-term Benzodiazepine UseFirst author,
year

Data Source

Study Design(include years)

Population

ExposurefOutcomes

Notable findings

Comments

Manthey, L., Lohbeck, M., Giltay, E. J., van Veena, T., Zitman, F. G., & Penninx, B. W. (2012). Correlates of benzodiazepine dependence in the Netherlands
Study of Depression and Anxiety. Addiction, 107, 2173-2182.
gMol, A. J., Gorgels, W. J., Oude Voshaar, R. C., Breteler, M. H., van Balkom, A. J., van de Lisdonk, E. H., Zitman, F. G. (2005). Associations ofbenzodiazepine craving with other clinical variables in a population of general practive patients. Comprehensive Psychiatry, 46, 353-360.

167

Reference ID: 4675389

Table F2. Articles Included in Literature Review: Social Influence on Misuse and Abuse of Benzodiazepine Drugs
First
Author, YearStudy
DesignandSampleSize

Time
PeriodStudy Population andInclusion Criteria

Topic Drug

Study Findings

Comments

Peters,2007 aQualitativeinterviews,(10 openended
questions),
N=46

Spring2004

Youth attending inpatient drug
treatment program in Texas,
self-identifying as current
alprazolam users

Alprazolam/
Xanax

High social approvaland peer pressure werecommon concepts
among the 27 common
themes identified by the
researchers.

Inclusion criteria did not
distinguish between use
and misuse or abuse.
Commonly identified
themes may reflect
questions asked rather
than prominent beliefsof the participants.

Qualitative
semistructured
interviews,
N=13

June
2012 toApril
2013

BenzodiazepineReported motivations
included: to feel stonedor relaxation, and to
avoid daily stressors.

This study did not reporta distinction of use frommisuse or abuse forstudy inclusion.
Participants attending
drug treatment centers
have history of regular,
high-dose
benzodiazepine use.

Murphy, 2017bInclusion criteria: ages 12 to
21 years, entered treatment
facility less than 5 days prior,have used alprazolam at least
once during the past 30 days.
Participants recruited fromsubstance misuse treatment
centers in Cork, Ireland.
Inclusion criteria required
participants to be currently
using benzodiazepines and lessthan 21 years of age or haveused benzodiazepines when
they less than 21 years of age.
All participants were between
18 and 21 years of age at thetime of the interview.

168

Reference ID: 4675389

Responses focused on
the effects ofbenzodiazepine misuse,such as effects onfamily life, negatives ofbenzodiazepine misuse,and effects on social
functions. There waslittle focus on peerpressure or social
influence on a desire tomisuse benzodiazepine.

Interviews were semistructured based on aninterview guide andinterviewer bias should
be considered. Interview
questions inquired about
all benzodiazepines.

aPeters RJ, Meshack AF, Kelder SH, Webb P, Smith D, Garner K. (2007) Alprazolam (Xanax) Use Among Southern Youth: Beliefs andSocial Norms Concerning Dangerous Rides on “Handlebars.” J. Drug Education, 37:4. 417-428.
bMurphy KD, Lambert S, McCarthy S, Sahm LJ and Byrne S. (2018) “You Don’t Feel”: The Experience of Youth Benzodiazepine Misuse
in Ireland, Journal of Psychoactive Drugs, 50:2, 121-128.

169

Reference ID: 4675389

APPENDIX G. PHARMACOVIGILANCE DATA AND DESCRIPTIONSAppendix G1. FDA Adverse Event Reporting System (FAERS)
FAERS is a database that contains information on adverse event and medication error reports
submitted to FDA. The database is designed to support FDA's postmarketing safety surveillance
program for drug and therapeutic biological products. The informatic structure of the databaseadheres to the international safety reporting guidance issued by the International Council on
Harmonisation. Adverse events and medication errors are coded to terms in the Medical
Dictionary for Regulatory Activities (MedDRA) terminology. The suspect products are coded tovalid tradenames or active ingredients in the FAERS Product Dictionary (FPD).
FAERS data have limitations. First, there is no certainty that the reported event was actually due
to the product. FDA does not require that a causal relationship between a product and event beproven, and reports do not always contain enough detail to properly evaluate an event. Further,
FDA does not receive reports for every adverse event or medication error that occurs with aproduct. Many factors can influence whether or not an event will be reported, such as the time a
product has been marketed and publicity about an event. Therefore, FAERS data cannot be used
to calculate the incidence of an adverse event or medication error in the U.S. population.

170

Reference ID: 4675389

Appendix G2. Drug Abuse Dependence and Withdrawal (SMQ) Preferred Terms Lists
Drug abuse dependence andwithdrawal (SMQ)
Broad SearchPreferred Terms

Narrow Search

Dopamine dysregulation syndrome; Drug abuse; Drug abuser; Drug dependence; Drug dependence,
antepartum; Drug dependence, postpartum; Drug use disorder; Drug use disorder, antepartum; Drug use
disorder, postpartum; Intentional overdose; Intentional product misuse; Maternal use of illicit drugs;
Neonatal complications of substance abuse; Substance abuse; Substance abuser; Substance dependence;
Substance use disorder; Drug withdrawal convulsions; Drug withdrawal headache; Drug withdrawal
maintenance therapy; Drug withdrawal syndrome; Drug withdrawal syndrome neonatal

Dopamine dysregulation syndrome; Drug abuse; Drug abuser; Drug dependence; Drug dependence,
antepartum; Drug dependence, postpartum; Drug use disorder; Drug use disorder, antepartum; Drug use
disorder, postpartum; Intentional overdose; Intentional product misuse; Maternal use of illicit drugs;
Neonatal complications of substance abuse; Substance abuse; Substance abuser; Substance dependence;
Substance use disorder; Accidental overdose; Dependence; Disturbance in social behaviour; Drugdetoxification; Drug diversion; Drug level above therapeutic; Drug level increased; Drug screen; Drug screen
positive; Drug tolerance; Drug tolerance increased; Drug tolerance decreased; Intentional product use issue;
Medication overuse headache; Narcotic bowel syndrome; Needle track marks; Overdose; Prescribed
overdose; Prescription drug used without a prescription; Prescription form tampering; Reversal of opiate
activity; Substance use; Substance-induced mood disorder; Substance-induced psychotic disorder; Toxicity tovarious agents; Drug withdrawal convulsions; Drug withdrawal headache; Drug withdrawal maintenancetherapy; Drug withdrawal syndrome; Drug withdrawal syndrome neonatal; Drug rehabilitation; Reboundeffect; Steroid withdrawal syndrome; Withdrawal arrhythmia; Withdrawal catatonia; Withdrawal syndrome

171

Reference ID: 4675389

Appendix G3. FAERS Line Listing of Direct Reports of Drug Abuse Dependence and Withdrawal with Benzodiazepine As a Single Drug
Substance

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25

Initial FDA
Received Date
7/8/1999
6/13/2001
6/14/2001
4/2/2002
11/26/2003
7/9/2004
7/21/1993
5/27/1994
4/22/2005
8/10/2005
8/16/2005
8/25/2005
8/29/2005
10/3/2005
11/3/2005
11/7/2005
11/9/2005
10/31/2006
11/7/2006
5/4/2007
6/18/2007
7/27/2007
9/5/2007
11/12/2008
12/24/2008

FAERS Case #*33040293665677
3667051
377919740360244171089
5016691
5121032
5790289585981158652145870254587166258921745921930592214859236166167935
6171230
6310586
63409076375367
64133916816025
6872127

Age(years)
24
51
32
35
36
48
68
39
29
56
Unknown
48
45
41
Unknown
45
34
41
27
42
76
49
37
66
36

Sex

Drug of Interest

FemaleFemaleFemaleMale
Male
FemaleMale
FemaleFemaleFemaleMale
FemaleFemaleFemaleFemaleMale
FemaleMale
FemaleFemaleMale
FemaleFemaleFemaleFemaleClonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam

172

Reference ID: 4675389

Country
Derived
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA

Serious
Outcome(s)†DS
RI, OTHO, DS, RI, OT
HO, LT, DS, RI, OT
DS, RI
DS, OTHOHO
HO, OT
HO, LT, RI
OTDS, OTHO, DS, OT
OTOTRI
HO, LT, OTOT
HO, OTOT
HO
RI
OT
LT, OT

26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55

10/16/2009
1/25/2010
2/26/2010
10/7/201010/17/2013
11/19/2013
8/4/2014
10/9/201410/31/2014
6/6/2016
6/21/2017
6/22/20176/24/2017
6/26/2017
7/1/2017
7/6/2017
7/11/2017
5/1/2019
4/27/1998
7/3/2001
9/4/2001
12/3/2002
1/14/2004
3/24/2004
7/22/1983
12/2/1988
3/14/1989
5/24/1989
10/6/1989
3/16/1990

7155001
72606907304445764243196320189697422
10366014
10510562
10560296
12442042
13677252
13681454
13689186
13693239
13711080
13725699
13744842
16263948
3133694
36766623707064
38723414072698
411527843838554632864464491646570644675592
4710419

21
47
45
45
30
53
54
53
46
61
38
56
48
45
37
41
41
54
41
58
Unknown
45
Unknown
33
56
64
39
39
Unknown
Unknown

Male
FemaleFemaleFemaleMale
FemaleFemale
Male
Male
Male
FemaleMale
FemaleFemaleFemaleFemaleFemaleMale
Male
FemaleFemaleMale
Male
FemaleFemaleFemaleFemaleFemaleNot Reported
Not Reported

173

Reference ID: 4675389

Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Clonazepam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam

USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
CAN
USA
USA
USA
USA
USA

LT, RI, OT
RI, OTOT
HO, LT, DS, RI, OT
HO, DS
DS, OTOTDSDSHOHO, DS
HO, LT, DS, OT
OT
LT, DSDS
HO, LT, DS
DS
LT, DSOTDS, RI, OT
OT
LT
DS
OT
HO
OT
OT
HO

56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85

4/24/1992
6/1/1993
8/14/1994
3/9/1995
2/17/2005
3/8/2005
4/8/2005
1/2/2007
3/26/2007
9/5/2007
8/25/2008
9/29/2008
7/30/2009
12/2/2009
1/25/2010
6/23/2017
7/2/2017
5/14/2003
9/1/1972
9/1/1972
9/1/1972
3/3/2009
4/19/2000
1/30/2001
5/21/2003
10/1/1981
5/31/1991
8/25/2005
8/29/2005
12/7/2005

4874072
5001135
5147944523181657496225758741577831962412186281537
6411690674220567795247081777
72003467260891
13688768
13710638
39486694269228
426924442693236935505
34645363604333
3951188434637047982995870280
58711465939177

41
35
57
41
46
38
Unknown
56
30
55
28
62
77
58
38
29
49
56
Unknown
Unknown
Unknown
31
49
57
68
Unknown
67
Unknown
71
53

Male
FemaleMale
FemaleMale
FemaleFemaleFemaleFemaleMale
FemaleFemaleMale
FemaleFemale
Male
Male
Male
Male
FemaleFemaleMale
Male
FemaleFemaleMale
Male
FemaleFemaleMale

174

Reference ID: 4675389

Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Alprazolam
Diazepam
Diazepam
Diazepam
Diazepam
DiazepamLorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam

USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA

HO, OT
OT
OTOT
LT
LT, OT
RI
LT, OTOT
HO, LT, RI, OT
HO, RI, OT
HOOT
HO, DS, OT
LT, DSOT
HO, LT, DS, RI
OTOTHODS, OT
OT
OT

86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104

2/27/2006
12/14/2006
10/18/2007
4/1/2009
9/23/200910/12/2011
2/6/2012
7/22/2014
9/11/201410/31/2014
10/31/2014
6/30/2015
6/23/2017
6/23/201712/17/2018
5/10/2004
5/13/1983
1/13/1989
5/21/2009

5999604
6203360645548969659117136030
8177082839141110335062
10449928
10559460
10560024
11230472
13688615
13688791
15731646
4140852438017946356197007367

57
36
55
50
51
31
55
34
17
43
38
46
58
55
25
34
Unknown
36
49

FemaleFemaleFemaleFemaleFemaleFemaleFemaleMale
FemaleFemaleFemaleFemaleFemaleMale
Male
FemaleNot Reported
FemaleFemaleLorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Lorazepam
Triazolam
Triazolam
TriazolamOxazepam

USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA

OT
OT
HO
LT
OT
DS
DS
LT
DS
DS
DS
HO, LT, OT
DS
HO, DS
RI, OTHOLT, DS, RI, OT*All FAERS cases in this case series are direct reports and have only one version; therefore, manufacturer control numbers and version nu†As per 21 CFR 314.80, the regulatory definition of serious is any adverse drug experience occurring at any dose that results in any of the following
outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent orsignificant disability/incapacity, or a congenital anomaly/birth defect, and other serious important medical events. Those which are blank were notmarked as serious (per the previous definition) by the reporter and are coded as non-serious. A case may have more than one serious outcome.
Abbreviations: DE=Death, HO=Hospitalization, LT= Life-threatening, DS= Disability, RI=Required Intervention, OT=Other Medically Significant

175

Reference ID: 4675389

Signature Page 1 of 2-------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically. Following this are manifestations of any and allelectronic signatures for this electronic record.
-------------------------------------------------------------------------------------------/s/-----------------------------------------------------------AMY E SEITZ
09/24/2020 11:54:11 AM
SARANRAT WITTAYANUKORN
09/24/2020 11:55:37 AM
SHEKHAR H MEHTA
09/24/2020 01:55:50 PM
KELLY M HARBOURT
09/24/2020 01:59:08 PM
SARA KARAMI
09/24/2020 02:04:38 PM
CHRISTINA R GREENE
09/24/2020 02:06:08 PM
ROSE G RADIN
09/24/2020 02:34:48 PM
CORINNE M WOODS
09/24/2020 02:46:50 PM
VICKY C CHAN
09/24/2020 02:59:00 PM
JANA K MCANINCH
09/24/2020 03:07:01 PM
RAJDEEP K GILL
09/25/2020 05:59:20 PM
For Travis Ready
CINDY M KORTEPETER
09/25/2020 09:27:02 PM
JUDY A STAFFA
09/26/2020 05:56:19 AM

Reference ID: 4675389

Signature Page 2 of 2

JUDY A STAFFA
09/26/2020 05:56:19 AM

Reference ID: 4675389