The n e w e ng l a n d j o u r na l of m e dic i n e
b o ok r e v ie w s
Prescribing by Numbers: Drugs
and the Definition of Disease
By Jeremy A. Greene. 318 pp., illustrated. Baltimore,
Johns Hopkins University Press, 2007. $49.95.
ISBN 978-0-8018-8477-1.
A t the dawn of the era of personal-
ized medicine, we are poised to understand
how patterns of genes and proteins can influence
the risk that a disease will develop in an asymptom-
atic person. We will determine the risk by calcu-
lating risk scores and categorizing patients on the
basis of those scores. The idea of quantifying risk
by means of numeric formulas and then labeling
asymptomatic persons as diseased is controver-
sial, but it is not a new concept. In Prescribing by
Numbers, Greene reviews the history of the treat-
ment of hypertension, diabetes, and hypercho-
lesterolemia and addresses the idea of treating
asymptomatic persons on the basis of quantitative
measures to prevent future health problems.
Greene describes the relationship between ad-
vances in treatment, the incentives of manufac-
turers, and the effect on the public of increased
attention to prevention. Science drives the devel-
opment of technology, which in turn drives the
development of science. With the power and ben-
efits of new technology, the opportunity to be
more aggressive than ever before in recruiting
at-risk patients for treatment or prevention has
changed standards of clinical practice. Clinical
benefits can be assumed, but quantification is dif-
ficult and raises many questions.
The riskbenefit trade-offs of the quantitative
approach are complex, and Greenes historical
revelations are timely. GlaxoSmithKlines drug
Avandia (rosiglitazone maleate) is now in the news
because of worries about cardiovascular events
related to its use in patients with diabetes. Twenty-
seven years before this finding, the use of tolbu-
tamide the first oral medication for diabetes
was curtailed when a clinical trial showed an
increased incidence of cardiovascular events. Con-
troversy between the manufacturer and the Food
and Drug Administration surrounding the label-
ing of this drug continued for almost 15 years.
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Today, we continue to treat the symptom of high
blood glucose in an effort to reduce the chance
of future cardiac events, but we are not always
certain of this result.
Another revelation in this book concerns the
history of commercial influences on clinical devel-
opment and the conflicts that can result. Given
current discussions about the influence of indus-
try in health care, it is perhaps worth acknowledg-
ing how far we have come. In 1958, an entire issue
of the Journal of the American Medical Association (JAMA)
was devoted to articles that detailed the efficacy
and safety of chlorothiazide. Readers might not
have known that the editor-in-chief of JAMA was
also the president of the Pharmaceutical Manu-
facturers Association (now called the Pharmaceu-
tical Research and Manufacturers of America).
Not discussed in Greenes book are the bene-
fits that patients have derived from the quantita-
tive approach to disease categorization. Complex
forces clearly will shape personalized medicine,
and the trade-off between risks and benefits may
not always be clear. We can look to previous ex-
periences from our evolving clinical guidelines to
anticipate challenges to come.
Kevin A. Schulman, M.D.
Duke University
Durham, NC 27715
Patients with Substance
Abuse Problems: Effective
Identification, Diagnosis,
and Treatment
By Edgar P. Nace and Joyce A. Tinsley. 224 pp. New York,
W.W. Norton, 2007. $22.95. ISBN 978-0-393-70511-9.
T he diagnosis and treatment of sub-
stance-abuse disorders are gaining the atten-
tion of physicians, and no wonder in a given
year, 9% of the U.S. population is found to be de-
pendent on or to abuse alcohol, and almost 4% are
dependent on illicit drugs. Nicotine dependence,
a licit and actually greater cause of illness and
 book reviews
death, affects some 20% of the population. Such
problems are now discussed in most medical
schools.
Psychiatry has a subspecialty certification for
expertise in addiction, and there is a growing body
of knowledge concerning how clinicians can and
should bring their patients from the stage of pre-
contemplation to the stage of action in dealing
with addiction. This approach, based on motiva-
tional interviewing, has been shown to be effec-
tive when used by generalists as well as addiction
specialists. Furthermore, material advances are
being made in the field of biomedicine toward
understanding the pathophysiology of addiction;
clarification of the neurologic mechanisms of
dependence and craving is especially important.
For example, in imaging studies, drug-seeking can
be seen to cause activation of the prefrontal cortex,
and glutaminergic projections from the prefron-
tal cortex to the amygdala and nucleus accumbens
are now understood to be instrumental in condi-
tioned drug craving.
The authors of Patients with Substance Abuse
Problems, both of whom are psychiatrists, set out
to write a coherent, relatively brief overview of
the field of substance abuse. They have dedicat-
ed their effort to the American Academy of Ad-
diction Psychiatry, but the book will be useful to
any practicing physician whether an internist
or a family-medicine practitioner and to gen-
eral psychiatrists as well. The book is not pon-
derous but is actually quite readable, and it ex-
presses the engaging voice of the authors rather
than the diverse and less consistent orientations
often found in edited multiauthored books.
The authors review a good deal of the salient
medical literature concerning the basics of addic-
tion and usefully detail specific procedures such
as detoxification schedules for alcohol, anxiolytic
and hypnotic agents, and opioids. All this mate-
rial is written with attention to understanding the
patients denial, the physicians need to maintain
a positive perspective, and the importance of what
the authors call staying with the patient. Because
the book is brief, however, the authors do not go
into detail about the genetics of addiction or spe-
cific approaches to treatment, such as facilitation
of a 12-step program, contingency management,
family and network therapy, and methadone main-
tenance.
The authors understand the need to relate ef-
fectively to the patient. This is perhaps the most
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important role of the physician who encounters a
patient with an addiction, because it is the main-
stay of what the physician can do at this point in
our understanding of alcohol and drug abuse.
Consider the treatment of alcoholism. Naltrexone,
an opioid antagonist, has been shown to dimin-
ish the alcohol consumption of patients. Even with
concomitant counseling, however, the effect of
oral naltrexone is modest relative to placebo, and
the recently approved depot naltrexone has only
limited acceptance among patients with alcohol-
ism. There are also questions regarding acampro-
sate, another drug recently approved for the treat-
ment of alcoholism. One major study, completed
after this book was written, failed to show a dif-
ference in outcome between active acamprosate
and placebo. Other medications that have been
studied off-label for use in the treatment of alco-
holism, such as topiramate and ondansetron, have
been of little use.
In the treatment of opioid addiction, buprenor-
phine, an opioid partial agonist, has been found
useful for both detoxification and maintenance.
It is being used to reduce dependence on narcotic
analgesic pills and heroin, but it cannot be pre-
scribed without appropriate psychosocial treat-
ment. Federal regulations require that its use be
accompanied by such treatment, but physicians
need to hone their skills in this area; many who
are certified to prescribe it appear to offer little,
if any, of the required counseling. We have no
systematic observations from community-based
practitioners on the long-term outcome of the use
of buprenorphine, and without proper, continuing
psychosocial treatment, patients may relapse to
opioid use or continue the abuse of other unrelated
substances. Furthermore, buprenorphine is sub-
ject to illicit diversion, a problem in some coun-
tries where it is widely prescribed.
The concept of addiction as a disease is appeal-
ing because it has countered the widely held view
of addiction as a willful behavior with moral im-
plications. Likening addiction to hypertension and
diabetes is also appealing because of addictions
chronicity and vulnerability to breakthrough symp-
toms. The rehabilitation of patients with sub-
stance-abuse problems has, however, been handled
largely by nonphysicians who work closely with
their patients; physicians have been more inclined
to treat the somatic consequences of addiction.
The medicalization of addiction can therefore dis-
tract the physician from the importance of treat-
517
 The new england journal of medicine

ing the addicted patient on the basis of a well-con-

ceived, helpful relationship. In tone and intent,
the authors of this book address this important
issue.
Marc Galanter, M.D.
New York University Medical Center
New York, NY 10024
marcgalanter@nyu.edu

Diagnosing Genius: The Life

and Death of Beethoven
By Franois Martin Mai. 270 pp., illustrated. Montreal,
McGillQueens University Press, 2007. $29.95.
ISBN 978-0-7735-3190-1.

F ranois Martin Mai is a psychiatrist

who has written an excellent book describing

Ludwig van Beethovens life, his health problems,
and how his illnesses may have influenced his cre-
ativity. Mai examines Beethovens inauspicious
childhood and lifelong chronic illnesses. By the
time he was 28 years old, Beethoven had already
become profoundly deaf, a circumstance that dam-
aged his self-esteem and jeopardized his profes-
sional and artistic future. His life was also made
miserable by chronic diarrhea, abdominal pain,
chronic respiratory illness, depression, and alco-
hol abuse. However, he made all these detrimen-
tal personal matters subservient to the composi-
tion of beautiful music.
Deafness was the most infamous of Beetho
vens illnesses, but its cause is still controversial.
Mai speculates that it was caused by otosclero-
sis, which is the most common cause of deafness
in young men. However, the high-frequency loss
described by Beethoven is not typical of the con-
dition, and for this reason Mais diagnosis is
doubtful.
The cause of Beethovens death was liver failure
due to alcohol abuse. The autopsy was performed
by Dr. Johann Wagner, who was assisted by Dr.
Karl von Rokitansky. Rokitansky was a resident in
pathology, and Beethovens autopsy was the first
one he performed. He subsequently performed
59,786 autopsies in his outstanding career as a
pathologist and became famous for his observa-
tions on the gross features of pathologic abnor-
malities of organs.
At Beethovens autopsy, Wagner and Rokitan-
Bettmann/Corbis.
Undated Lithograph of Beethoven Composing
the Missa Solemnis.
sky found besides cirrhosis of the liver due to
alcohol abuse ascites, splenomegaly, pancreati-
tis, and thickened bones of the skull. The eighth
cranial nerves were wrinkled and shriveled be-
cause they had been compressed by the thick skull
bones, a finding consistent with Pagets disease
of bone, which can cause deafness. Other condi-
tions that have been put forth as the cause of
Beethovens deafness including head trauma
inflicted by his alcoholic father, syphilis, and oto-
sclerosis lack credibility. There is also some
question of whether lead poisoning caused Bee
thovens illnesses. In 1996, a lock of his hair was
found to contain high levels of lead. Lead poison-
ing was common in Europe during Beethovens
time because wine contained lead that had leached
from its containers.
Beethoven is an icon of classical music. His
music has the power to ennoble the human spirit
and to evoke a heroic spirit in the struggle against
adversity and oppression. At the time of his death,
Beethoven was at the height of his powers as a
composer. Mai believes that Beethoven had bipo-
lar depression; at times he was suicidal, and he
was hypomanic he could compose several dif-
ferent works simultaneously. In his Symphony
no. 3 in E-flat Major, Eroica, there is a sudden

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