in Practice

The History of Benzodiazepines

After more than 50 years of experience with benzodiazepines, the American health care system has a love-hate relationship with
them. In 1955, Hoffmann-La Roche chemist Leo Sternbach serendipitously identified the first benzodiazepine, chlordiazepoxide
(Librium). By 1960, Hoffmann-La Roche marketed it as Librium, and it pursued molecular modifications for enhanced activity.
Valium (diazepam) followed in 1963. Hoffmann-La Roches competitors also began looking for analogues. Initially, benzodiazepines
appeared to be less toxic and less likely to cause dependence than older drugs. A specific improvement was their lack of
respiratory depression, a safety concern with barbiturates. Medical professionals greeted benzodiazepines enthusiastically at
first, skyrocketing their popularity and patient demand. In the mid-to-late 1970s, benzodiazepines topped all most frequently
prescribed lists. It took 15 years for researchers to associate benzodiazepines and their effect on gamma-aminobutyric acid as a
mechanism of action. By the 1980s, clinicians earlier enthusiasm and propensity to prescribe created a new concern: the specter
of abuse and dependence. As information about benzodiazepines, both raising and damning, accumulated, medical leaders and
legislators began to take action. The result: individual benzodiazepines and the entire class began to appear on guidelines and
in legislation giving guidance on their use. Concurrently, clinicians began to raise concerns about benzodiazepine use by elderly
patients, indicating that elders lesser therapeutic response and heightened sensitivity to side effects demanded prescriber caution.
The benzodiazepine story continues to evolve and includes modern-day issues and concerns beyond those ever anticipated.

Key Words: Barbiturates, Benzodiazepines, Chlordiazepoxide, Diazepam, Elderly, Hoffmann-La Roche, Medicare, Prescription
drug abuse, Sternback, Tranquilizer.

Abbreviations: CSA = Controlled Substances Act, GABA = Gamma-aminobutyric acid, MOA = Mechanism of action,
STP = Sewage treatment plant.

Jeannette Y. Wick

The History of Benzodiazepines At the Beginning

F
act, opinion, controversy, triviabenzodiazepine
history is full of all of these. After more than
50 years of experience with this drug class, the
American health care system has a love-hate relationship
with them. Are they miracle drugs that save lives and
ameliorate suffering, or do they shatter lives and alter
cognition, making them malevolence in a bottle? That
depends on the circumstances, source, and ultimate user.
Hoffmann-La Roche chemist Leo Sternbach identified
the first benzodiazepine, chlordiazepoxide (Librium), in
1955. Hoffmann-La Roche had a keen interest in finding
better tranquilizers. Regardless, an ideal candidate eluded
their research team for years, and management decided to
abandon their disappointing efforts. Sternbachan inde-
pendent, bulldog of a scientist and a notoriously messy
personwas frustrated. His desire to continue looking for
a tranquilizer was in direct opposition to the companys

538 The Consultant Pharmacist september 2013 Vol. 28, No. 9

plan. Told to move on, he left his laboratory mess intact.
Two years later, management directed him and others
on his team to clean his cluttered lab space. Sternbachs
coworker Earl Reeder noticed a nicely crystalline com-
pound (RO-5-0690) that had not been tested in previous
trials. Sternbach had synthesized this benzoheptoxdiazine
as a young researcher in dye-stuff chemistry. The com-
pound sat on his cluttered bench for more than 20 years.1,2
Sternbach, unwilling to give up on finding a better
tranquilizer, submitted RO-5-0690 for a standard battery
of animal tests, expecting negative results, but thinking
they might be able to publish chemistry-related findings.
Within days, the tests demonstrated that the compound
chlordiazepoxidehad notable anticonvulsant, muscle
relaxant, and sedative effects. By 1960, Hoffmann-La
Roche marketed it as Librium, and the research team
pursued molecular modifications for enhanced activity.1,3-5
Valium (diazepam), stamped with its trademark V and
named based on the Latin valere (be strong), followed
in 1963. Both drugs were tremendously successful,
largely replacing older sedatives and hypnotics by 1970.6,7
Hoffmann-La Roches competitors also began looking
for analogues.
Medical professionals greeted benzodiazepines enthu-
siastically at first, skyrocketing their popularity and patient
demand. Valium was so popular that physicians just
called it V. Other pharmaceutical firms developed new
and slightly different benzodiazepines, using each drugs
unique strengths to carve out market niches (Table 1).
In addition to those approved in the United States, many
were approved elsewhere (Table 2). The hypnotic fluni-
trazepammarketed under the trade name Rohypnol in
other countrieswas also a Sternbach molecule. Although
an excellent drug for insomnia, it has achieved worldwide
notoriety as a date-rape drug (discussed below). In the
mid-to-late1970s, benzodiazepines topped all most fre-
quently prescribed lists, becoming global sensations with
around 40 billion doses consumed annually.8
Benzodiazepine prescribing peaked in 1978 and 1979,
with Americans consuming 2.3 billion Valium tablets
in each of those years.7,10 By the 1980s, clinicians earlier
enthusiasm and propensity to prescribe created a new
concern: the specter of abuse and dependence. Prescribers
The Consultant Pharmacist september 2013 Vol. 28, No. 9 539
were disillusioned, and the general publics view was split.
Some embraced these drugs for their ability to provide
relief for disabling back pain and seizures. Others believed
that many addicts were innocent victims whose legitimate
need turned into a nightmare of craving and inability
to stop taking the drugs. Still others abused these drugs
recreationally, starting the largest and longest episode of
prescription drug misuse in history.7
After more than 50 years of experience with this
drug class, the American health care system has a
love-hate relationship with benzodiazepines.
Molecular Magic
To understand how benzodiazepines infiltrated the
Americanand globalmedical systems and societal
structures, we can start with the pharmacological puzzles
of most importance in the 1950s. Few drugs were available
to treat mental illness. For centuries, humans had used
opium and alcohol to self-medicate. Psychiatrists also used
these drugs to attempt to treat patients with mental illness,
but rarely saw any significant improvement.11
With the discovery of chlorpromazine, hope grew
that clinicians might have a medicine cabinet of drugs to
address nervous and mental disorders. Until then, the only
drugs available to treat anxiety, depression, and insomnia
were chloral hydrate, reserpine, and the barbiturates.
Chloral hydrates use was limited by concerns about
dependence. It also often caused acute toxicities mani-
fested by nausea, vomiting, confusion, convulsions, slow
and irregular breathing, and cardiac arrhythmia, progress-
ing to coma. Reserpine has many side effects, including
disabling nightmares. Although researchers didnt know it
at the time, two other available drug classesbarbitu-
rates and meprobamatehad some receptor activity in
common with the yet-to-be-discovered benzodiazepines.
Barbiturates, with sleepiness and somnolence as serious
side effects, were also habit-forming. Accidental and
suicidal overdose were common.5,11 Marilyn Monroe and
Judy Garland were among many whose lives were taken by
 The History of Benzodiazepines

Table 1. Benzodiazepines Currently Approved in the United States and Uses

Benzodiazepine FDA Approval FDA-Approved Indication Off-Label Uses

Chlordiazepoxide 1960 Alcohol-withdrawal syndrome
Anxiety
Preoperative anxiety
Diazepam 1963 Alcohol-withdrawal syndrome Anesthesia adjunct
Anxiety Benzodiazepine withdrawal
Sedation, premedication Sedation for mechanically
before surgery, endoscopic ventilated patients in
procedures, and cardioversion intensive care units
Seizure:
o Adjunct
o Refractory, increased
frequency
o Status epilepticus
Skeletal muscle spasm
o Adjunct
o Tetanus
Oxazepam 1965 Alcohol-withdrawal syndrome Insomnia
Anxiety

Clorazepate 1972 Alcohol-withdrawal syndrome Epilepsy

dipotassium Anxiety
Partial seizure; adjunct

Clonazepam 1975 Panic disorder Restless leg syndrome

Seizure Sleepwalking disorder
Social phobia

540 The Consultant Pharmacist september 2013 Vol. 28, No. 9

 Table 1. Benzodiazepines Currently Approved in the United States and Uses (continued)

Benzodiazepine FDA Approval FDA-Approved Indication Off-Label Uses

Lorazepam 1977 Anxiety AgitationPsychotic disorder
Insomnia, a result of anxiety or Alcohol-withdrawal syndrome
situational stress Chemotherapy-induced
Premedication for anesthetic nausea and vomiting;
procedure prophylaxis
Status epilepticus Sedation
Seizure
Seizure, drug-induced;
prophylaxis
Alprazolam 1981 Anxiety disorder Alcohol-withdrawal
Panic disorder with or without syndrome
agoraphobia Depression
Temazepam 1981 Insomnia Anxiety
Triazolam 1982 Insomnia Jet lag
Flurazepam 1985 Insomnia
Midazolam 1985 Anxiety Etomidate adverse reaction
Induction of amnesia Myoclonia

Preoperative sedation Insomnia

Induction of general anesthesia Postoperative nausea and

vomiting
Procedural sedation
Seizure
Sedation for a mechanically

ventilated patient
Quazepam 1985 Insomnia
Estazolam 1990 Insomnia
Clobazam 2011 Lennox-Gastaut syndrome Alcohol-withdrawal syndrome
(a difficult-to-treat form of Anxiety
childhood epilepsy); adjunct

Source: Reference 9.

Abbreviation: FDA = Food and Drug Administration.

The Consultant Pharmacist september 2013 Vol. 28, No. 9 541

 The History of Benzodiazepines

Benzodiazepine use in psychiatric and seizure disor-

Table 2. Benzodiazepines Approved ders grew quickly. Clinicians found their muscle relaxant
Outside of the United States qualities superior to other available drugs, and patients
with back pain found relief. Soon, formal studies and
Bromazepam informal empiric prescribing found them useful in insom-
Cloxazolam nia, panic disorders, and phobias. By the mid-1960s, their
Cinolazepam utility in managing alcohol and barbiturate withdrawal was
Flunitrazepam clear.14-16 Physicians began to prescribe them for conditions
that previously had not been treated with prescription
Flutoprazepam
medication: stress, garden-variety anxiety, and nervous-
Halazepam
ness. Often, physicians prescribed the benzodiazepines for
Ketazolam
months or years.
Loprazolam
Lormetazepam Solved: The MOA Mystery
Medazepam It took 15 years for researchers to associate benzodi-
Nimetazepam azepines and gamma-aminobutyric acid (GABA), the
Nitrazepam mammalian central nervous systems principal inhibitory
Nordazepam transmitter. In 1977, Mhler and Okada identified what
Phenazepam they called benzodiazepine receptorssaturable sites
Pinazepam that were stereoselective and had high affinity for these
Prazepam drugs. Using a series of benzodiazepines, they determined
Premazepam that displacing the drug from its binding site improved
Tetrazepam the drugs anxiolytic and anticonvulsant potencies.17 In
the following year, another researcher was able to prove
that benzodiazepines facilitate GABA-ergic synapses.18,19
Additional research has identified benzodiazepine
barbiturate overdose. The alternative was Carter-Wallaces
receptor subtypes. Alpha 1 is responsible for sedative and
Miltown (meprobamate), a popular tranquilizer that was
amnestic effects. Alpha 2 and alpha 3 have anxiolytic and
also habit-forming, plagued with neurologic side effects,
muscle-relaxing effects. Alpha 1, alpha 2, and alpha 5 have
and lethal in overdose with as little as 12 g.11,12 Finding a
anticonvulsant effects. The alpha 5 subtype may also have a
safe, effective class of drugs became a focus for all phar-
role in pain relief. By enhancing GABAs inhibitory activity,
maceutical manufacturers.
benzodiazepines reduce excitatory neurotransmitters,
Chlordiazepoxide and diazepam filled that need.
including norepinephrine, serotonin, dopamine, and
Initially, they appeared to be less toxic and less likely
acetylcholine centrally.20,21
to cause dependence than the older drugs. A specific
Around that same time, reports of benzodiazepine
improvement was their lack of respiratory depression, the
addiction began to surface.23-27 These reports indicated that
primary concern with barbiturates. They were much less
people were abusing benzodiazepines alone in large doses,
likely to cause death in overdose unless combined with
or with other drugs or alcohol (thereby increasing the risk
something else.13 Researchers couldnt identify their spe-
of a serious outcome). They also noted that benzodiaz-
cific mechanism of action (MOA), but continued to look
epines were being sold illegally in the streets.
for it. They knew that finding the MOA would explain
previously unknown brain chemistry.

542 The Consultant Pharmacist september 2013 Vol. 28, No. 9

 The History of Benzodiazepines
A Culture of Chemical Coping
Among the benzodiazepines, Valium became a cultural
star, and its ubiquitous presence gave way to a plethora of
humor and slang. Consider a scene from the 1979 movie
Starting Over: Burt Reynoldss character suffers a panic
attack in Bloomingdales. As he hyperventilates, his brother
shouts, Does anyone have a Valium? Dozens of women
reach into their purses and extract prescription vials.
Reynolds, in several interviews, noted this scene was based
on a real incident.28
In 1967, The Rolling Stones immortalized the house-
wifes Valium use in Mothers Little Helper, singing:
She goes running for the shelter
Of a mothers little helper
And it helps her on her way
Gets her through her busy day.
Indeed, it was not just women who used Valium.
Corporate jet-setters called it Executive Excedrin for its
ability to help them cope with travel across time zones.28
Valiums dark side was also worked its way into books.
Jacqueline Susanns 1966 blockbuster Valley of the Dolls
described how ambitious career girls self-medicated with
Valium to cope with New York Citys cruelties (Dolls
referred not to the women, but was originally slang
for dolophine, and then came to mean more generally,
barbiturates and downers).29 Barbara Gordons biography
and subsequent movie Im Dancing as Fast as I Can
documented her crippling anxiety attacks as a high-profile
television producer, which led to diazepam addiction.30
Today, the media still give benzodiazepines starring
roles, and like barbiturates before them, theyve been
associated with celebrity addiction and death. Elizabeth
Taylor admitted addiction to diazepam and alcohol, and
benzodiazepines were implicated in the deaths of both
Anna Nicole Smith (although it was concurrent chloral
hydrate that caused her death) and Heath Ledger. Many
popular crime dramas have helped make people aware of
benzodiazepines and their addiction potential, and the
television show Law & Order: SVU in particular has
aired episodes about flunitrazepam, or Roofies, as a date-
rape drug. This drug, when slipped surreptitiously into
an alcoholic beverage, induces drowsiness, impairs motor
544 The Consultant Pharmacist september 2013 Vol. 28, No. 9
skills, and causes anterograde amnesia. The rape victim is
unaware that shes been violated. When its manufacturer
(Hoffmann-La Roche) realized that rapists were using
flunitrazepam in the late 1990s, they altered the tablet to
make it less likely to dissolve and included a dye that turns
beverages blue.31-33 Some researchers believe that the con-
cern about flunitrazepam is overblown, and that the most
common date-rape drug is actually alcohol.34,35
In general, health care practitioners now agree
that prescribers should avoid benzodiazepines for
older adults.
Changing an Entire Social System
By 1990, prescribers worldwide wrote 18 million prescrip-
tions for benzodiazepines. Benzodiazepines were at the
root of the United Kingdoms largest-ever class action
lawsuit against the drug industry. Approximately 14,000
patients and 1,800 law firms alleged pharmaceutical firms
that manufactured benzodiazepines (e.g. Hoffmann-
LaRoche, Wyeth, and Upjohn) intentionally suppressed
information about dependence potential from physicians.
They alleged that manufacturers extensive marketing and
promotion coupled with medical schools training tradi-
tion (that de-emphasized adverse events) compounded
the problems. As the UKs court system struggled with
the unwieldy suit, individual patients sued 117 general
practitioners and 50 health authorities for damages related
to dependence and withdrawal.10,36
The consequences were far-reaching. Some British
physicians began requiring patients to sign consent forms
that described dependence and withdrawal risks before
they would prescribe benzodiazepines.10 Amid allegations
that expert witnesses had conflicts of interest and lawyers
decisions to withdraw from the case, the case was dropped.
British law was changed forever, however, and modified to
make class-action lawsuits more difficult.36
 Table 3. Lists and Laws Addressing Benzodiazepines
Target Benzodiazepine Lists or Laws and Their Purposes

Diazepam, lorazepam, midazolam World Health Organization Essential Drugs: A list of drugs meant to
satisfy the health needs of the majority of the population that should be
available at all times and in sufficient amounts in key hospital settings.

Flunitrazepam Drug-Induced Rape Prevention and Punishment Act of 1996: Amends

Alprazolam, chlordiazepoxide,
diazepam, lorazepam, triazolam
the Controlled Substances Act (CSA) to impose penalties of up to
20 years imprisonment and a fine for violating CSA provisions by
distributing a controlled substance to an individual without that
individuals knowledge, with intent to commit a crime of violence
(including rape) against such individual.
National Institute on Drug Abuses Commonly Abused Prescription
Drugs Chart: List of prescription drugs commonly abused and provides
their common and street names, routes of administration, and potential
health effects.

All benzodiazepines The 2003 Medicare Modernization Act: A public law that overhauled
Medicare and created an entitlement benefit for prescription
drugs starting in 2006. It excluded all benzodiazepines, regardless
of diagnosis or justification. Only Medicare beneficiaries with
supplemental drug insuranceas dual-eligibles or having private
secondary insurancehave access to benzodiazepines.
All benzodiazepines Patient Protection and Affordable Care Act of 2010: Creates significant
government expansion and regulatory overhaul of the U.S. health care
system. Includes language that prevents any health care plan, including
Medicare, from excluding benzodiazepines.

All benzodiazepines
Source: References 38-43.
The American Geriatrics Society 2012 Beers Criteria Update: Identifies
drugs that, when used in older patients, are associated with poor
outcomes. This document recommends avoiding benzodiazepines for
treatment of anxiety, delirium, or insomnia. It also includes situations in
which benzodiazepines may be useful.

Leadership, Lists, Laws
As information about benzodiazepinespraising and
damningaccumulated, medical leaders and legislators
began to take action. The result: individual benzodiaz-
epines and the entire class began to appear on lists and
in laws describing their use (Table 3). These documents,
some indicating that benzodiazepines are essential and
helpful, others suggesting grave danger by excluding the
entire class, reflect the tremendous conflict that surrounds
this drug class. Of note, the Affordable Care Act negated
the 2003 Medicare Modernization Acts exclusion of
benzodiazepines, once again making them available to

The Consultant Pharmacist september 2013 Vol. 28, No. 9 545

 The History of Benzodiazepines
Medicare beneficiaries in January 2013 for all medically
acceptable indications. Some clinicians think that this will
lead to overprescription and abuse in the geriatric popula-
tions unless appropriate controls are developed.37
Least Benefit, Greatest Risk?
Concurrently, clinicians began to raise concerns about
benzodiazepine use by elderly patients, indicating that
elders lesser therapeutic response and heightened
sensitivity to side effects demanded prescriber caution
(Table 4).43-48 The medical literature has established
associations between long-term benzodiazepine use and
increased risk of cognitive impairment, delirium, falls, and
fractures. Many elders who have serious anxiety, however,
respond well to benzodiazepines.13,43
Over time, clinicians working with elders have come to
prefer the short-to-intermediate-acting benzodiazepines
(e.g., oxazepam and temazepam) when they are needed,
and experts recommend prescribing them for short-term
use only. When possible, they used alternatives like
zaleplon and zolpidem (which work on benzodiazepine
receptors, but are molecularly distinct) and low doses
of sedating antidepressants.50 In general, health care
practitioners now agree that prescribers should avoid ben-
zodiazepines for older adults. Certain conditions, however,
respond well to benzodiazepines, and the benefits may
outweigh the risks. End-of-life anxiety and perioperative
anesthesia are two such conditions. Benzodiazepines also
have a role in treating spasticity associated with cerebral
palsy in developmentally disabled children and adults and
for seizure ablation (diazepam rectal gel).9,43
Sorting It Out
Decades later, benzodiazepines have raised even more
questions. Why do we have benzodiazepine receptors?
What purpose do they serve? Are anxiety and insomnia
related to substances that occupy benzodiazepine recep-
tors in the way that diabetes follows insulin sensitivity or
deficiency? Patients who have two conditionsidiopathic
recurrent stupor and hepatic encephalopathyhave been
found to have benzodiazepine-like compounds called
endozepines in their systems, indicating that this system
546 The Consultant Pharmacist september 2013 Vol. 28, No. 9
Table 4. Concerns: Continued
Benzodiazepine Use by the Elderly and
Associated Risks
Increased risk of dependence, especially
with the high-potency benzodiazepines
(e.g., alprazolam, triazolam)
Increased sensitivity to adverse effects
including memory problems, daytime
sedation, impaired motor coordination
Increased risk of motor vehicle accidents
and falls
Progressively worsening long-term effects
resembling dementia, depression, or
anxiety syndromes
Source: References 44-50.
may be like the insulin/diabetes condition and can go
haywire.22,51,52 Researchers who study evolution think that
benzodiazepine receptors developed late. Their role may
be to allow relaxation after a fright/flight reaction, or to
control internal benzodiazepine-inverse agonists in an
antagonistic way.21,52 Anxiety and panic disorders may
be a disruption in these functions. Perhaps as we know
more about these systems, scientists will be able to develop
compounds that target specific areas, and provide relief
without side effects or addiction potential.
Conclusion
This paper has covered fact, opinion, and controversy.
Benzodiazepines, perhaps more than any other class
of modern drug, have been recognized and disdained,
appreciated and attacked. Sternbach died in 2008. Using
chemistry as his tool, he devoted his life to helping others.
His goal in developing these drugs was humanitarian in
nature. Sternbach always objected to the vilification of the
class and any intervention that made it more difficult for
people who needed benzodiazepines to get them. Used
appropriately, benzodiazepines are highly effective.
Used recreationally, and especially with alcohol or
other drugs, they can lead to serious consequences.
Perhaps the most significant case in U.S. medical history
was that of Karen Ann Quinlan. She took a diazepam-
alcohol overdose, and remained in a comaa persistent
vegetative statefor 10 years while her family worked
through the court systems to be allowed to disconnect
her supportive care. The courts ultimate ruling allow-
ing her family the right to discontinue treatment gave
patients and families the right to live with dignity and
respect. It also established the impetus for medical
institutions to establish and maintain ethics committees.
The Quinlan case created the concept of living wills and
advanced directives that allow individuals to indicate
their choices at end of life.55 Clearly, benzodiazepines
have had a far-reaching role in how medicine is practiced.
Finally, one piece of trivia sums up the scope
and challenges of current benzodiazepine use. Trace
pharmaceutical drug residues have been found in many
bodies of water worldwide.53 Very recently, scientists in
Sweden found that fish living downstream from sewage
treatment plants (STP) had elevated benzodiazepine
levels. These drugs, excreted from humans, had survived
the STPs ordinary scrubbing system and indicate that
their use is widespread. When they exposed captive fish
to levels similar to those that they found in downstream
waters, perch became less fearful, more antisocial, more
active, and are better forgerers. The scientists indicate
wild fish populations may be affected similarly, and have
no idea how these trace levels affect humans.54 Thus, the
benzodiazepine story will evolve and continue to evolve
to include modern-day issues and concerns beyond those
ever anticipated. n
The Consultant Pharmacist september 2013 Vol. 28, No. 9 547
Jeannette Y. Wick, RPh, MBA, FASCP, is a visiting professor at the
University of Connecticut School of Pharmacy, Storrs, Connecticut,
and a freelance medical writer in Arlington, Virginia.
Disclosure: No funding was received for the development of this
manuscript. The author has no potential conflict of interest.
Consult Pharm 2013;28:538-48.
2013 American Society of Consultant Pharmacists, Inc.
All rights reserved.
Doi:10.4140/TCP.n.2013.538.
References
1. Baenninger A, Costa e Silva JA, Hindmarch I et al. Good Chemistry:
The Life and Legacy of Valium Inventor Leo Sternbach. New York, NY:
McGraw-Hill; 2003.
2. Sternbach LH. The discovery of librium. Agents Actions 1972;2:193-6.
3. Sternbach LH. The benzodiazepine story. J Med Chem 1979;22:1-7.
4. Miller NS, Gold MS. Benzodiazepines: reconsidered. Adv Alcohol
Subst Abuse 1990;8:67-84.
5. Sternbach LH. The discovery of Librium. Agents Actions 1972;2:193-6.
6. Shorter E (2005). Benzodiazepines: A Historical Dictionary of
Psychiatry. Oxford, UK: Oxford University Press; 2005:41-2.
7. U.S. News & World Report. Leo Sternbach: the father of mothers little
helper. 1999;127:58.
8. Ashton H. The diagnosis and management of benzodiazepine
dependence. Curr Opin Psychiatry 2005;18:249-55.
9. Benzodiazepines. Drug Facts and Comparisons. Facts & Comparisons
[database online]. St. Louis, MO: Wolters Kluwer Health, Inc; April 2013.
Accessed May 15, 2013.
10. Marks J. The benzodiazepines: an international perspective. J Psycho-
active Drugs 1983;15:137-49.
11. Berger FM. The significance of laboratory studies in the evaluation
and discovery of psychoactive agents in man. Dis Nerv Syst 1969;30
Suppl:5-10.
12. Balon R. The dawn of anxiolytics: Frank M. Berger, 1913-2008. Am J
Psychiatry 2008;165:1531.
13. Dalen JE. The effects of diazepam. Anesthesiology 1969;31:196-7.
14. Armour PS. Management of acute alcohol and barbiturate withdrawal
states. West Med J West 1963;4:369-70.
15. Kissen MD. Management of psychomotor agitation in acute
alcoholism: a double-blind study using chlordiazepoxide. Dis Nerv Syst
1965;26:364-8.
16. Wegner ME, Fink DW. Chlordiazepoxide (Librium) compared with
meprobamate and promazine (Prozine) for the withdrawal symptoms of
acute alcoholism. Wis Med J 1965;64:436-40.
17. Mhler H, Okada T. Benzodiazepine receptor: demonstration in the
central nervous system. Science 1977;198:849-51.
18. Haefely W. Involvement of GABA in the actions of neuropsychotropic
drugs. Int J Neurol 1979;13:53-66.
19. Haefely WE. Central actions of benzodiazepines: general introduction.
Br J Psychiatry 1978;133:231-8.
 The History of Benzodiazepines
20. Guerrini G, Ciciani G. Benzodiazepine receptor ligands: a patent
review (2006-2012). Exp Opin Ther Pat 2013 March 24. [Epub ahead
of print]
21. Munro G, Hansen RR, Mirza NR. GABA(A) receptor modulation:
potential to deliver novel pain medicines? Eur J Pharmacol 2013 March
13. [Epub ahead of print]
22. Avallone R, Zeneroli ML, Venturini I et al. Endogenous
benzodiazepine-like compounds and diazepam binding inhibitor
in serum of patients with liver cirrhosis with and without overt
encephalopathy. Gut 1998;42:861-7.
23. Woody GE, OBrien CP, Greenstein R. Misuse and abuse of diazepam:
an increasingly common medical problem. Int J Addict 1975;10:843-8.
24. Misra PC. Nitrazepam (Mogadon) dependence. Br J Psychiatry
1975;126:81-2.
25. Bliding A. The abuse potential of benzodiazepines with special
reference to oxazepam. Acta Psychiatr Scand Suppl 1978;274:111-6.
26. Greenblatt DJ, Shader RI. Dependence, tolerance, and addiction to
benzodiazepines: clinical and pharmacokinetic considerations. Drug
Metab Rev 1978;8:13-28.
27. Physical dependence on benzodiazepines? Drug Ther Bull 1977;15:
85-6.
28. Marantz Heinz R. Valiums contribution to our new normal.
September 29, 2012. Available at http://www.nytimes.com/2012/09/30/
sunday-review/valium-and-the-new-normal.html?_r=0. Accessed April
15, 2013.
29. Susann J. Valley of the Dolls. 6th ed. New York, NY: Grove Press; 1997.
30. Gordon B. Im Dancing as Fast as I Can. 2nd ed. New York, NY:
Moyer Bell; 2011.
31. Ledray LE. Date rape drug alert. J Emerg Nurs 1996;22:80.
32. Anglin D, Spears KL, Hutson HR. Flunitrazepam and its involvement
in date or acquaintance rape. Acad Emerg Med 1997;4:323-6.
33. Weir E. Drug-facilitated date rape. CMAJ 2001;165:80.
34. Hurley M, Parker H, Wells DL. The epidemiology of drug facilitated
sexual assault. J Clin Forensic Med 2006;13:181-5.
35. Hindmarch I, ElSohly M, Gambles J et al. Forensic urinalysis of drug
use in cases of alleged sexual assault. J Clin Forensic Med 2001;8:197-205.
36. Peart R. Memorandum by Dr Reg Peart. Minutes of Evidence. Select
Committee on Health, House of Commons, UK Parliament. Available
at http://www.publications.parliament.uk/pa/cm199899/cmselect/
cmhealth/549/99072723.htm. Accessed April 2, 2013.
37. Prabhakar D. Preparing for a benzodiazepine tsunami. Psychiatry
(Edgmont) 2009;6:12.
38. World Health Organization. WHO model list of essential medications.
17th list, March 2011. Available at http://whqlibdoc.who.int/hq/2011/
a95053_eng.pdf. Accessed April 4, 2013.
39. Public Law No: 104-305. Drug-Induced Rape Prevention and
Punishment Act of 1996. Available at http://thomas.loc.gov/cgi-bin/
bdquery/z?d104:HR04137:@@@L&summ2=m&. Accessed April 4, 2012.
548 The Consultant Pharmacist september 2013 Vol. 28, No. 9
40. Ong MK, Zhang L, Xu H et al. Medicare Part D benzodiazepine
exclusion and use of psychotropic medication by patients with new
anxiety disorders. Psychiatr Serv 2012;63:637-42.
41. Patient Protection and Affordable Care Act of 2010, Pub. L.
No. 111-148, 2502, 124 Stat. 119, amended by Health Care and
Education Reconciliation Act of 2010, Pub. L. No. 111-152, 124 Stat.
1029 (to be codified as amended at 42 U.S.C. 1396r-8(d)) (adding
benzodiazepines to drugs that cannot be excluded).
42. National Institute on Drug Abuse. Commonly abused prescription
drugs chart. October 2011. Available at http://www.drugabuse.gov/
drugs-abuse/commonly-abused-drugs/commonly-abused-prescription-
drugs-chart. Accessed April 4, 2013.
43. American Geriatrics Society 2012 Beers Criteria Update Expert
Panel. American Geriatrics Society updated Beers criteria for potentially
inappropriate medication use in older adults. J Am Geriatr Soc
2012;60:616-31.
44. Keston M, Brocklehurst JC. Flurazepam and meprobamate: a clinical
trial. Age Ageing 1974;3:54-8.
45. Rummans TA, Davis LJ Jr, Morse RM et al. Learning and memory
impairment in older, detoxified benzodiazepine-dependent patients.
Mayo Clin Proc 1993;68:731-7.
46. Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short
elimination half-life and the risk of hip fracture. JAMA 1989;262:3303-7.
47. Cummings SR, Nevitt MC, Browner WS et al. Risk factors for hip
fracture in white women. Study of Osteoporotic Fractures Research
Group. N Engl J Med 1995;332:767-73.
48. Barbone F, McMahon AD, Davey PG et al. Association of road traffic
accidents with benzodiazepine use. Lancet 1998;352:1331-6
49. an Strien AM, Koek HL, van Marum RJ, et al. Psychotropic
medications, including short acting benzodiazepines, strongly increase
the frequency of falls in elderly. Maturitas 2013;74:357-62.
50. Huedo-Medina TB, Kirsch I, Middlemass J et al. Effectiveness of
non-benzodiazepine hypnotics in treatment of adult insomnia: meta-
analysis of data submitted to the Food and Drug Administration. BMJ
2012;345:e8343.
51. Baraldi M, Avallone R, Corsi L et al. Natural endogenous ligands for
benzodiazepine receptors in hepatic encephalopathy. Metab Brain Dis
2009;24:81-93
52. Gou ZH, Wang X, Wang W. Evolution of neurotransmitter gamma-
aminobutyric acid, glutamate and their receptors. Dongwuxue Yanjiu
2012;33:E75-81.
53. Wick JY. Limiting pharmacys environmental footprint. Consult
Pharm 2003;18:747-59.
54. Brodin T, Fick J, Jonsson M et al. Dilute concentrations of a
psychiatric drug alter behavior of fish from natural populations. Science
2013;339:814-5.
55. Karen Ann Quinlan Memorial Foundation. Karen Ann Quinlan,
1954-1985. Available at http://www.karenannquinlanhospice.org/history/.
Accessed May 15, 2013.