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1
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Library of Congress Cataloging-​in-​Publication Data

Names: Peppin, John F., editor. | Pergolizzi, Joseph V., Jr., editor. |
Raffa, Robert B., editor. | Wright, Steven L., editor.
Title: The benzodiazepines crisis : the ramifications of an over-used drug class/
​senior editor, John F. Peppin ; editors, Joseph V. Pergolizzi Jr.,
Robert B. Raffa, Steven L. Wright.
Description: New York, NY : Oxford University Press, [2021] |
Includes bibliographical references and index.
Identifiers: LCCN 2020025885 (print) | LCCN 2020025886 (ebook) |
ISBN 9780197517277 (paperback) | ISBN 9780197517291 (epub) |
ISBN 9780197517307 (online)
Subjects: MESH: Anti-​Anxiety Agents | Benzodiazepines—​adverse effects |
Substance Withdrawal Syndrome
Classification: LCC RM666. B42 (print) | LCC RM666. B42 (ebook) |
NLM QV 77.9 | DDC 615.7/​882—​dc23
LC record available at https://​lccn.loc.gov/​2020025885
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This material is not intended to be, and should not be considered, a substitute for medical or other
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individual circumstances. And, while this material is designed to offer accurate information with respect
to the subject matter covered and to be current as of the time it was written, research and knowledge
about medical and health issues is constantly evolving and dose schedules for medications are being
revised continually, with new side effects recognized and accounted for regularly. Readers must therefore
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To Professor C. Heather Ashton, DM FRCP (1929–​2019)
It was all very well to say “Drink me,” but the wise little Alice was not going to do that in a hurry.
“No, I’ll look first,” she said, “and see whether it’s marked ‘poison’ or not.”
—​Lewis Carroll, Alice in Wonderland
CONTENTS

Overview ix
Foreword: Addiction xi
A. J. Reid Finlayson
Foreword: Pain xiii
Lynn Webster
Foreword: Patient Advocacy xvii
Bernie Silvernail
Foreword: Patient xix
Carrie Silvernail
Preface xxiii
John F. Peppin, Joseph V. Pergolizzi Jr., Robert B. Raffa, and Steven L. Wright
Contributors xxv
Benzodiazepines: A Chronology xxvii

1. Introduction: The Origins and Rise of Benzodiazepines 1

Michael M. Miller and John F. Peppin
2. The Evolution of Benzodiazepine Receptor Agonists: Developments in
Pharmacology and Toxicology 6
Jamie L. Hansen and Timothy J. Atkinson
3. Benzodiazepine Therapy: The Good, the Bad, and the Ugly 17
Jeffrey Guina, Brian Merrill, and Jo Ann LeQuang
4. Use of Benzodiazepines and Z-​Drugs in the Geriatric Population 41
Jan M. Kitzen
5. The Central Benzodiazepine Receptor 68
Michael H. Ossipov
6. Benzodiazepine Receptors in the Periphery 81
Robert B. Raffa
 7. Drug Withdrawal: A Modern Motivational View and Neurobiological
Substrates 97
George F. Koob
8. Benzodiazepine Withdrawal: Clinical Aspects 117
Steven L. Wright
9. Benzodiazepines and Pain Management 149
John F. Peppin and Steven L. Wright
10. The Regulatory History of Benzodiazepines in the Age of the Dark Web and
Other Threats 160
John J. Coleman
11. Benzodiazepines Today and Tomorrow: What We Know and Don’t Know About
Them 193
John J. Coleman
12. In Search of Benzodiazepine Guidelines 216
Jo Ann LeQuang
Conclusion 237
John F. Peppin, Joseph V. Pergolizzi Jr., Robert B. Raffa, and Steven L. Wright

Disclosure Agreements 239

Index 241

[ viii ] Contents
OVERVIEW

• Benzodiazepines were developed to treat legitimate medical needs. However, unbri-

dled success and prescribing beyond their intended duration of use and the available
data have led to excessive prescribing, extended utilization beyond good therapeutic
practice, and unintended adverse effects and substance use disorder.
• This book is the first to bring to light and discuss the largely unrecognized and
enigmatic problem of an exceedingly prolonged withdrawal syndrome from
benzodiazepines that can persist for months or years in susceptible patients, the
medical need for better evidence-​based prescribing of benzodiazepines, and a call
for the recognition and better treatment of the prolonged withdrawal syndrome.
• Unfortunately, many of the negative aspects of benzodiazepines and their ineffective
or unsafe use (e.g., to treat pain or concomitant use with opioids) are not widely
known, but the potential extreme duration of the withdrawal syndrome is virtually
unknown to most healthcare providers and to regulatory agencies.
• Most healthcare prescribers believe that benzodiazepines produce one and only one
pharmacologic effect: positive allosteric modulation of GABA A receptors located
in the brain. Unfortunately, the simplicity of this belief has distracted researchers,
clinicians, and regulators from studying and appreciating the negative consequences
of the prolonged use of these drugs—​and even other aspects of their pharmacology.
A glaring example is an almost universal lack of awareness of peripheral benzodiaze-
pine receptors. The peripheral benzodiazepine receptors affect mitochondrial func-
tion (energy supply), cholesterol transport, and immune function.
• Therefore, there exists a significant and pressing medical and societal need for an
updated overview of benzodiazepine physiology, pharmacology, side effects, and
abuse potential, as well as clinical efficacy and application.
• All stakeholders involved in the use of benzodiazepines (e.g., psychiatrists, primary
care physicians, pain physicians, substance use disorder health care practitioners,
regulatory, legislative, hospice and palliative care healthcare providers, and patients)
should benefit from the information contained in this book.
FOREWORD: ADDICTION
A . J. REID FINL AYSON, MD
Vanderbilt University Medical Center, Nashville, TN, USA

This book is a much-​needed compilation and examination of the risks and benefits of
the long-​term use of benzodiazepine drugs. Named to elicit thoughts of equilibrium,
peaceful valleys, rest, relaxation and halcyon days, benzodiazepine minor tranquilizers
provide safer sedation than the barbiturates that were in general use 60 years ago.
Although these drugs are approved for use in seizure disorders, generalized anxiety,
and panic disorders, benzodiazepines are no longer considered first-​line treatment. The
benzodiazepine class of sedating drugs carries significant risks that involve depression,
dependence, addiction, amnesia, and overdose death, especially when combined with
other agents that affect the central nervous system. Benzodiazepines are useful in emer-
gency settings and operating theaters and to avert the consequences of withdrawal from
alcohol and sedating drugs.
The illicit use of benzodiazepines is quite common because the medications have
been generally believed to be safe. Minor tranquilizers have also become popularized as a
safe solution to many varieties of the unpleasant feelings of distress that often accompany
growth-​promoting change in life circumstance. Increasingly, chronic benzodiazepine use
appears to be detrimental to patients with chronic psychiatric illnesses and substance
use disorders. Once thought to be protective against suicidal impulses, benzodiazepines
are more often associated with suicide and overdose deaths. Benzodiazepine abuse is
common among persons who abuse other substances, particularly opioids. Also, reports
of forged benzodiazepine tablets containing fentanyl confirm the strength of the illicit
demand for these still widely prescribed and available controlled substances.
The debate about the advantages of prescribing benzodiazepines over psychologic
treatment modalities (e.g., cognitive-​ behavioral therapy, acceptance commitment
therapy, various psychotherapies) is ending for common emotional symptoms like in-
somnia and anxiety disorders. Additionally, there may be perverse logic in reserving
chronic benzodiazepine prescribing for the severely mentally ill. Disagreement persists
about the advantages of chronic benzodiazepine prescription for schizophrenia, bipolar
illness, and complex posttraumatic stress disorder. These are populations in which rel-
evant randomized controlled trials are rare and disagreement about benzodiazepine
efficacy abounds. Allowing that debate to remain unresolved rationalizes support for
chronic prescribing at the expense of extremely vulnerable patient populations.
There are similarities to consider and lessons to learn from the role of pharmaceutical
industry promotion in the current opioid crisis. In America, managed care facilitates
benzodiazepine prescribing by providing increased reimbursement of physicians for
prescribing medication that exceeds psychotherapy reimbursement. Since attending a
Swiss Upjohn conference on alprazolam (Xanax) in the early 1990s, I have witnessed
first-​hand how market forces actively influence medical practice by obfuscating negative
results.
This book assembles the best evidence-​based information to guide caring and sup-
port for patients who are continuing long-​term benzodiazepine use and may wish to
stop. Physicians should learn to apply this knowledge to avoid unintended consequences
of legislative prescribing regulations similar to those that have occurred in the manage-
ment of chronic pain.

[ xii ] Foreword: Addiction

FOREWORD: PAIN
LYNN WEBSTER , MD
Vice President Scientific Affairs, Neurosciences
PRA Health Sciences, Salt Lake City, UT, USA

How can it be that a book like this has not been previously published? It is surprising,
considering the length of time benzodiazepines have been around and the problems
associated with them.
Over the past 50 years, more than 2,000 different benzodiazepines have been devel-
oped, but only about 15 are currently approved by the Food and Drug Administration
in the United States.
The current opioid crisis has overshadowed the contribution of benzodiazepines to
our larger drug crisis. The title of a 2018 New England Journal of Medicine commentary
by Lembke et al., “Our Other Prescription Drug Problem,” shines a light on the benzodi-
azepine stealth crisis of the last half century—​and the problem is not unique to America.
A study of six European countries (Belgium, France, Italy, Germany, the Netherlands,
and Spain) found that anxiolytics, including benzodiazepines, were the most commonly
used psychotropic drugs in these countries, with an overall prevalence of 9.8%.1 In
fact, a 2006 study showed that 12.5% of people 18 and older in France were prescribed
benzodiazepines.2 The common use of benzodiazepines has also been reported in
Canada,3 Australia,3 Finland,3 Thailand,4 and Brazil.4 Surprisingly to many, Japan has
been reported to have the highest consumption rate of benzodiazepines in the world.5
Between 1996 and 2013, the quantity of benzodiazepines prescriptions filled by
adults in the United States increased by 67%, from 8.1 million to 13.5 million.6 A 2008
study showed that benzodiazepines were prescribed twice as often for women as for
men.7 This may be due to attitudes toward women in society more than an absolute in-
crease in anxiety with females.
Benzodiazepines have been extraordinarily beneficial for millions of people with
anxiety disorders. However, clinical problems occur wherever benzodiazepines have
been prescribed, although they are less widely acknowledged than those caused by other
drugs. The lack of attention paid to the risks of benzodiazepines increases their danger.
That is why this book is so desperately needed, and so timely.
I cannot think of editors who are more highly qualified to tell the story we need to
hear. They have assembled authors who cogently explain the reality of the use and abuse
of benzodiazepines. The information provided in this book is obviously important for
all clinicians, but it is also very instructive for a public that increasingly demands more
facts about the medications prescribed to them.
This is not the first avant-​garde academic publication by senior editor John F. Peppin.
I first learned of his academic prowess through his international expertise in medical
ethics. That is not the subject of this book, but it certainly contributes to the reason he
has championed a book on this topic. He is an authority in many areas, with deep roots
in clinical medicine and research. A palliative care physician and scholar, Peppin is a pro-
lific author who has penned or edited some of the most-​cited publications in the field
of pain medicine on topical analgesics, opioid-​induced constipation, urine drug testing,
and opioid abuse.
Co-​editors Joseph Pergolizzi and Robert Raffa are equally well known and prolific.
Between them, they have written more than 500 peer-​reviewed publications including
books, chapters, and manuscripts. This diverse group of editors produces informative,
science-​based, and clinically meaningful content.

THE ROOT OF THE PROBLEM

It may be useful to briefly examine why benzodiazepines have been so commonly prescribed
and abused. For better or worse, benzodiazepines have been the gold standard for pharma-
cologic treatment of anxiety, despite the growing problem of their abuse and misuse—​and
people appear to have more anxiety and stress now than at any time in our history.
At the turn of the twentieth century, approximately 60% of the American popu-
lation lived in rural areas.8 By 2018, only 18% of the population remained on farms.9
Most people who lived in rural areas early in the twentieth century channeled their anx-
iety into physically demanding jobs, which mitigated their stress. Urban and suburban
dwellers can go to the gym and eat the right foods, but that isn’t enough. Sedentary
lifestyles and crowded conditions in less rural communities have been associated with
an increase in stress.10
There are numerous other factors that contribute to an individual’s ability to cope
with stress; for example, approximately 20% of veterans of recent wars experience
posttraumatic stress disorder.11 These factors and many more help to explain why
benzodiazepines have become so widely prescribed.

THE CONSEQUENCES OF BENZODIAZEPINES

According to the National Institute on Drug Abuse, overdose deaths involving

benzodiazepines rose between 1999 and 2017, from 1,135 to 11,537.12 Despite
this trend, the adverse effects of benzodiazepine overuse, misuse, and addic-
tion continue to go largely unacknowledged. Three-​quarters of deaths involving
benzodiazepines also involve an opioid,13 which may explain why, in the context of
a widely recognized opioid problem, the dangers associated with benzodiazepines
have been overlooked.

[ xiv ] Foreword: Pain

 We only have to scan news stories about many high-​profile deaths in recent
years to see that benzodiazepines were often a major contributor. The presence of
benzodiazepines apparently played a role in the deaths of Anna Nicole Smith, Heath
Ledger, Amy Winehouse, Whitney Houston, and many others, despite uncertainty
about the exact causes of their demise.
Death is only one potential consequence of benzodiazepine misuse; unfortunately,
there are others. For example, benzodiazepines have also been used as “date rape” drugs.
Bill Cosby was convicted of using Quaaludes, which are similar to benzodiazepines, to
incapacitate his victims.
And not least on our list of concerns is the fact that benzodiazepines amplify the
effects of opioids on respiratory depression. It wasn’t until about 2004 when I (and I
believe most other physicians) became aware that benzodiazepines could render lethal
what would otherwise be a safe dose of an opioid.
A sleep specialist made me aware that chronic opioid therapy could cause an ab-
normal breathing pattern, which he described as “biots breathing,”14 during sleep. This is
an irregular (similar to the rhythm of atrial fibrillation) breathing pattern and a form of
sleep-​disordered breathing.
I was puzzled and didn’t know what to believe, because the American Pain Society and
the American Academy of Pain Medicine had published a statement in 1996 that stated,
“Respiratory depression induced by opioids tends to be a short-​lived phenomenon, gen-
erally occurs only in the opioid-​naive patient, and is antagonized by pain. Therefore,
withholding the appropriate use of opioids from a patient who is experiencing pain on
the basis of respiratory concerns is unwarranted.”15
This seemingly conflicting information led me to do a study. What I discovered was
new to most of us in the field and very disturbing. Although the focus of the study was
on opioids, the more profound observation was the contribution benzodiazepines had
on creating life-​threatening sleep-​disordered breathing.16
In this study, combining a benzodiazepine with an opioid dramatically increased the
risk of central sleep apnea. Usually, central sleep apnea is limited to people with neurologic
disorders or advanced cardiac disease. These conditions were not generally present among
my pain patients. Furthermore, there were no clinical signs to warn me that patients could
have a life-​threatening condition due to co-​prescribing opioids with benzodiazepines.
It took a few years, but eventually, other scientific literature began to report sim-
ilar findings. As a result, some professionals now suggest that benzodiazepines are
contraindicated when opioids are prescribed. I believe that may be an overreach, for
reasons Gary Reisfield explained in the 2013 publication, “Benzodiazepines in Long-​
Term Opioid Therapy.”17 However, in recent years, benzodiazepines have deservedly
been prescribed with more caution to patients using opioids.
Today, more than ever, providers are expected to understand the risks of drugs
that can be abused—​while formal medical education has failed to provide that under-
standing. Patients, too, are asking for a more thorough understanding of the trade-​offs
and possible consequences involved in the use of these drugs.
In the quest to help ensure these valuable drugs are used as safely as possible, benzo-
diazepine prescribers and users alike will be well directed by this book.

Foreword: Pain [ xv ]
REFERENCES

1. Ohayon, M. M., Lader, M. H. (2002). Use of psychotropic medication in the general popu-
lation of France, Germany, Italy, and the United Kingdom. Journal of Clinical Psychiatry, 63,
817–​825.
2. Rosman, S., Marc, L. V., Nathalie, P. -​F. (2011). Gaining insight into benzodiazepine
prescribing in general practice in France: A data-​based study. BMC Family Practice, 12, 28.
Retrieved from http://​doi.org/​10.1186/​1471-​2296-​12-​28.
3. Hartikainen, S., Rahkonen, T., Kautiainen, H., Sulkava, R. (2003). Kuopio 75+ study: Does
advanced age predict more common use of psychotropics among the elderly? International
Clinical Psychopharmacology, 18, 163–​167.
4. Horta, B. L., de Lima, M. S., Faleiros, J. J., Weiderpass, E., Horta, R. L. (1994).
Benzodiazepines: prescription study in a primary health care unit. Revista da Associação
Medica Brasileira, 40, 262–​264.
5. Uchida, H., Suzuki, T., Mamo, D. C., Mulsant, B. H., Kikuchi, T., Takeuchi, H., Tomita, M.,
Watanabe, K., Yagi, G. (2009). Benzodiazepine and antidepressant use in elderly patients with
anxiety disorders: a survey of 796 outpatients in Japan. Journal of Anxiety Disorders, 23, 477–​481.
6. Bachhuber, M. A., Hennessy, S., Cunningham, C. O., Starrels, J. L. (2016). Increasing
benzodiazepine prescriptions and overdose mortality in the United States, 1996–​2013.
American Journal of Public Health, 106(4), 686–​688. doi:10.2105/​A JPH.2016.303061
7. Olfson, M., King, M., Schoenbaum, M. (2015). Benzodiazepine use in the United States.
JAMA Psychiatry, 72(2), 136–​142. doi:10.1001/​jamapsychiatry.2014.1763
8. Hoyt, J. (2019, April 29). 1800–​1990: Changes in urban/​rural U.S. population. Senior Living.
Retrieved from https://​www.seniorliving.org/​history/​1800-​1990-​changes-​urbanrural-
​us-​population/​
9. World Bank. (n.d.). Rural population (% of total population). Retrieved from https://​data.
worldbank.org/​indicator/​sp.rur.totl.zs
10. Teychenne, M., Costigan, S. A., Parker, K. (2015). The association between seden-
tary behaviour and risk of anxiety: a systematic review. BMC Public Health, 15, 513.
doi:10.1186/​s12889-​015-​1843-​x
11. Gradus, J. L. (2019). U.S. epidemiology of PTSD. U.S. Department of Veteran Affairs.
Retrieved from https://​www.ptsd.va.gov/​professional/​treat/​essentials/​epidemiology.asp
12. National Institute on Drug Abuse. (2019). Overdose death rates. Retrieved from https://​
www.drugabuse.gov/​related-​topics/​trends-​statistics/​overdose-​death-​rates
13. Bachhuber, M. A. Hennessy, S., Cunningham, C. O., Starrels, J. L. (2016). Increasing
benzodiazepine prescriptions and overdose mortality in the United States, 1996–​2013.
American Journal of Public Health, 106, 686–​688.
14. Walker, J., Farney, R. J., Rhondeau, S. M., Boyle, K. M., Valentine, K., Cloward, T. V.,
Shilling, K. C. (2007). Chronic opioid use is a risk factor for the development of central
sleep apnea and ataxic breathing. Journal of Clinical Sleep Medicine, 3(5), 455–​461.
15. Approved by the American Academy of Pain Medicine Board of Directors on June 29,
1996. Approved by the American Pain Society Executive Committee on August 20, 1996.
16. Webster, L. R., Choi, Y., Desai, H., Webster, L., Grant, B. J. B. (2008). Sleep-​disordered
breathing and chronic opioid therapy. Pain Medicine, 9(4), 425–​ 432. doi:10.1111/​
j.1526-​4637.2007.00343.x
17. Reisfield, G. M., Webster, L. R. (2013). Benzodiazepines in long-​term opioid therapy. Pain
Medicine, 14(10), 1441–​1446. doi:10.1111/​pme.12236

[ xvi ] Foreword: Pain

F O R E W O R D : P AT I E N T A D V O C A C Y
BERNIE SILVERNAIL
President, Alliance for Benzodiazepine Best Practices
www.benzoreform.org

Our journey into the “dark side” of benzodiazepines began about nine years ago. After
intermittent use of alprazolam for anxiety and misdiagnosed atrial fibrillation, my wife
Carrie, an RN, through her own research discovered that the strange and confusing
symptoms she was experiencing were actually due to benzodiazepine withdrawal syn-
drome (BZWS). Our subsequent journey through the medical system left us frustrated
and confused. We consulted over a dozen prescribers, and none of them had heard of
BZWS. But all were willing help with what they knew: prescribing other medications,
often other benzodiazepines, to help with symptom management. We eventually
located a benzo-​wise naturopath, but by then Carrie was well into a self-​administered
plan for tapering off of her benzodiazepine prescriptions. We discovered that there are
thousands of BZWS sufferers who have had similar experiences, who have found their
way out of the dark via the twisty unreliable path of website-​based support groups.
We were looking for a way to prevent this from happening to others when we attended
the International Benzodiazepine Symposium in 2017 and met its founder Marjorie
Merit-​Carmen, who is also a BZWS sufferer. In addition, we met authors Steven L. Wright,
MD, and Robert Raffa, PhD, and several other “benzo-​wise” medical professionals and
BZWS sufferers. This was the genesis of the Alliance for Benzodiazepine Best Practices,
a nonprofit organization that is dedicated to providing evidence-​based benzodiazepine
and Z-​drug (collectively benzodiazepine receptor agonists [BzRAs]) information to
prescribers and patients. None of the funding for the Alliance comes from pharmaceu-
tical companies, with the majority coming from “benzo survivors” and their loved ones.
We have an admitted bias: the evidence shows that benzodiazepines and Z-​drugs are
usually harmful when used for more than two to four weeks, and we want this induced
suffering to stop.
Why is a small nonprofit leading this charge toward evidence-​based prescrip-
tion? In the last 20 years the Food and Drug Administration and Drug Enforcement
Administration have received over 300,000 BzRA complaints and noted over 65,000
deaths in the system they set up to protect the public (MedWatch), yet they have not
investigated these drugs. There has been little grant money for academic research into
these drugs for several years, and none of it focused on the withdrawal and recovery
problem. There are hundreds of scientific papers and books and thousands of personal
stories and videos on the Internet, all connecting BzRAs to protracted withdrawal and
suicide. Yet prescriptions of these drugs continue to increase, a trend that the makers of
BzRAs are motivated to maintain.
This is a David-​and-​Goliath story with a couple of dozen grassroots organizations
and the evidence of harm on one side and over $3 billion of annual benzodiazepine and
Z-​drug sales and more lobbyists than members of the US Congress on the other. When
prescribed and used correctly, these drugs can be lifesavers. When not, they can be life-​
destroyers. This book presents the case for both sides, not just the arguments but the
research basis, controversies, and gaps in knowledge. BzRAs have been in use for over
70 years, yet you will see how much and how surprisingly little is known about them.
Even such basic questions as “What is the endogenous ligand of the benzodiazepine re-
ceptor?” have no accepted answer. Like the 1990s’ “new generation” of opioids, BzRAs
are generally considered “safe and effective,” yet there is a trail of suicides and destroyed
lives in the wake of their use. Even worse than the opioids, this book presents the evi-
dence that shows that BzRAs can produce long-​lasting neural damage.
Carrie has slowly healed since she finished her taper four years ago, but she is far from
fully recovered. Thousands of others have, usually without help from their prescriber,
determined the source of their persistent and ever-​shifting symptoms. They suffer along
with her. But they are almost certainly the lucky minority who had the tenacity and
background to figure this out on their own. The vast majority still suffer in the dark.
Our hope is that this book can bring the light of understanding to their prescribers and,
through them, relief to current sufferers and avoidance of the creation of new sufferers.

[ xviii ] Foreword: Patient Advocacy

F O R E W O R D : P AT I E N T
CARRIE SILVERNAIL

The story in this foreword describes in some detail the suffering of an individual patient
in her goal of removing benzodiazepines from her life. It reflects in very personal terms
the significant downside of an overused drug class. The editors would thank Carrie for
her willingness to share her story and her agreement to have her name published in this
volume.
Carrie Silvernail is a registered nurse by training and profession, living in Oregon,
where she raised her children and now enjoys her grandchildren. Her story begins with
some frightening runs of rapid heart rate without apparent reason a number of years ago.
As a nurse, she knew the name of her condition (tachycardia) and understood that it can
be dangerous, even life-​threatening in some cases. She went to a doctor who diagnosed
her with generalized anxiety disorder. The doctor prescribed 0.25 mg of alprazolam
(Xanax®), which she was to take only as needed. Carrie was the perfect patient; she
knew a lot about the drug and knew that benzodiazepines could cause dependence.
She also knew she might develop tolerance to the drug if she took it too often. She was
very careful to take only a little of the drug and only when necessary. She embarked
on a stress-​reduction regimen that included stress management techniques, more ex-
ercise, mindfulness meditation, yoga, and other natural ways to restore her emotional
equilibrium.
“I used it theee for years,” Carrie reported. “Sparingly. Less than directed.” The
benzodiazepines did nothing to help her tachycardia, and she was later diagnosed with
atrial fibrillation. She eventually underwent an ablation that cured the arrhythmia.
Unfortunately, at this point Carrie had a new problem. She had developed pelvic pain
that waxed and waned, migrated around the body, and was sometimes diffuse and some-
times very localized. The pelvic pain was “weird” because the symptoms came from out
of nowhere. Carrie eventually had a multidisciplinary team of clinicians look into these
symptoms. Her clinical team included a neurologist and a gynecologist, and she under-
went multiple diagnostic tests, including a lumbar magnetic resonance imaging scan, a
pelvic ultrasound, and several other tests. Although the test results all came back normal,
for Carrie, nothing was normal anymore.