The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Correspondence
Legalized Physician-Assisted Suicide
in Oregon, 2001
To the Editor: Although physician-assisted suicide has
been a legal option for terminally ill residents of Oregon
since 1997,1 it remains highly controversial. On November
6, 2001, U.S. Attorney General John Ashcroft issued a new
interpretation of the Controlled Substances Act prohibit-
ing the use of federally controlled substances to hasten
death. The state of Oregon filed a lawsuit against the U.S.
government to challenge Ashcrofts decision. Because of a
temporary restraining order in U.S. district court, the law
remains in effect pending a hearing by mid-April.
As follow-up to previous reports,2-4 we compared the
number and characteristics of patients who died in 2001
after ingesting legally prescribed lethal medications in Or-
egon with those of patients who died between 1998 and
2000. Patients were identified through required reports
filed by physicians on prescriptions for lethal medications.
Data were obtained from these reports, from interviews with
physicians, and from death certificates. We also compared
patients who chose physician-assisted suicide in 2001 with
Oregon residents who died in 2000 from similar underly-
ing diseases without physician-assisted suicide.
In 2001, 33 physicians in Oregon wrote 44 prescrip-
tions for lethal doses of medication (range, 1 to 4 prescrip-
tions). This number of prescriptions represents an increase
from 24 in 1998, 33 in 1999, and 39 in 2000. The number
written each month ranged from three to eight, with no
temporal trends noted over the course of the year. Of the
44 patients who received prescriptions, 19 died after ingest-
ing the medications, 14 died from their underlying disease,
and 11 were alive on December 31, 2001. During 1998,
1999, and 2000, 16, 27, and 27 patients, respectively, died
after ingesting lethal medications. Two patients who re-
ceived prescriptions during 2000 died after ingesting their
medications in 2001.
The 21 patients who chose physician-assisted suicide
during 2001 represent a rate of 7 per 10,000 deaths in Or-
egon similar to the rates of 6 per 10,000 in 1998, 9 per
10,000 in 1999, and 9 per 10,000 in 2000. The demo-
graphic characteristics of patients who ingested lethal med-
ications during 2001 resembled those of the patients who
died during previous years (Table 1). The exception was
that a slightly higher percentage of the patients were wom-
en, although this difference was not statistically significant.
As in previous years, those who chose physician-assisted sui-
cide in 2001 were more likely to have a college education
than other Oregon residents who died of similar underlying
illnesses (38 percent vs. 13 percent).
The lethal medications ingested during 2001 differed
from those used in previous years. Between 1998 and 2000,
67 of the 70 patients (96 percent) were given a prescription
for secobarbital, 2 were given a prescription for pentobar-
bital, and 1 was given prescriptions for other medications.
Eli Lilly (Indianapolis) stopped producing secobarbital in
May of 2001. In 2001, 16 of the 21 patients (76 percent)
were given a prescription for secobarbital, and 5 (24 per-
cent) were given a prescription for pentobarbital; 4 of
these 5 patients received their prescriptions during the last
three months of the year.
One of the 33 physicians who wrote prescriptions dur-
ing 2001 was reported to the Board of Medical Examiners
for submitting incomplete written consent. Twenty patients
died at home, and one died in an acute care hospital with
the hospitals permission. Prescribing physicians were present
while nine of the patients ingested the medication. One pa-
tient vomited after ingesting the medication and died 25
hours later; another patient lived for 37 hours after ingest-
ing the medication. Neither patient regained conscious-
ness, nor were emergency medical services called. No oth-
er complications were reported.
We conclude that in 2001, although the number of pre-
scriptions written for use in physician-assisted suicide in
Oregon was greater than in other years, the number of pa-
tients who ingested lethal medications remained small.

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 C ORR ES POND ENCE

TABLE 1. CHARACTERISTICS OF PATIENTS IN OREGON WHO DIED AFTER INGESTING

LEGALLY PRESCRIBED LETHAL MEDICATIONS AND OF ALL PATIENTS WHO DIED
FROM SIMILAR UNDERLYING ILLNESSES.*

PATIENTS WHO DIED

FROM SIMILAR
UNDERLYING
PATIENTS WHO DIED AFTER ILLNESSES
CHARACTERISTIC INGESTING LETHAL MEDICATIONS IN 2000 (N=6365)

2001 19982000
(N=21) (N=70)

Age yr
Median 68 70 75
Range 5187 2594 24105
Race no. (%)
Non-Hispanic white 20 (95) 68 (97) 6138 (96)
Asian 1 (5) 2 (3) 65 (1)
Male sex no. (%) 8 (38) 36 (51) 3325 (52)
Marital status no. (%)
Married 8 (38) 32 (46) 3249 (51)
Widowed 5 (24) 17 (24) 1965 (31)
Divorced 7 (33) 16 (23) 905 (14)
Never married 1 (5) 5 (7) 238 (4)
Level of education no. (%)
Less than high-school graduation 3 (14) 7 (10) 1541 (24)
High-school graduation or some college 10 (48) 32 (46) 3905 (62)
College graduation 8 (38) 30 (43) 850 (13)
Underlying illness no. (%)
Cancer 18 (86) 52 (74) 4949 (78)
Other disease 3 (14) 18 (26) 1416 (22)
Process of physician-assisted suicide
Referred for psychiatric evaluation no. (%) 3 (14) 20 (29)
Died at home (own, familys, or friends) 19 (95) 63 (90)
no. (%)
Medication prescribed no. (%)
Secobarbital 16 (76) 67 (96)
Pentobarbital 5 (24) 2 (3)
Other 0 1 (1)
Physician present when medication ingested 9 (43) 38 (54)
no. (%)
Vomiting or seizures after medication ingested
no. (%)
Vomiting or medication regurgitated 1 (5) 1 (2)
Seizures 0 0
Neither 20 (95) 65 (98)
Unknown 0 4
Days between initial request for medication
and death
Median 54 40
Range 15466 15377
Interval between ingestion of medication
and unconsciousness
Median min 3 5
Range min 130 138
Unknown no. 0 16
Interval between ingestion of medication
and death
Median min 25 30
Range 5 min37 hr 4 min26 hr
Unknown no. 0 11

*Data were obtained from death certificates and interviews with physicians. Patients for whom data
were missing were not included in the calculations of the percentages shown.
This category includes cancers of the liver, pancreas, bronchus or lung, skin, peritoneum, breast,
ovary, prostate, tonsil, and bladder, as well as non-Hodgkins lymphoma and myelodysplastic syndrome.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
The lack of availability of secobarbital has led physicians to
prescribe other barbiturates.
KATRINA HEDBERG, M.D., M.P.H.
DAVID HOPKINS, M.S.
KAREN SOUTHWICK, M.D., M.P.H.
Oregon Department of Human Services
Portland, OR 97232
katrina.hedberg@state.or.us
1. Oregon Death with Dignity Act, Oregon Revised Statute 127.800-
127.995. (See http://www.ohd.hr.state.or.us/chs/pas/pas.htm.)
2. Chin AE, Hedberg K, Higginson GK, Fleming DW. Legalized physi-
cian-assisted suicide in Oregon the first years experience. N Engl J Med
1999;340:577-83.
3. Sullivan AD, Hedberg K, Fleming DW. Legalized physician-assisted sui-
cide in Oregon the second year. N Engl J Med 2000;342:598-604.
4. Sullivan AD, Hedberg K, Hopkins D. Legalized physician-assisted sui-
cide in Oregon, 1998-2000. N Engl J Med 2001;344:605-7.
Deep-Brain Stimulation in Parkinsons Disease
To the Editor: The Deep-Brain Stimulation for Parkin-
sons Disease Study Group (Sept. 27 issue)1 reported the
results of a prospective, double-blind, crossover study in
patients with advanced Parkinsons disease, in whom elec-
trodes were implanted in the subthalamic nucleus or pars
interna of the globus pallidus and who then underwent bi-
lateral high-frequency deep-brain stimulation. In the Dis-
cussion section, the authors wrote: Although initiation of
stimulation was associated with transient symptoms in some
patients, we do not believe that this influenced the blinded
assessment, since neither the patients nor the investigators
were certain of whether stimulation was being given at the
time. In 1998, some of the same authors reported, with
respect to a double-blind evaluation of deep-brain stimula-
tion of the subthalamic nucleus in eight of the same pa-
tients, that all patients were able to guess which assess-
ments were performed with the stimulators on.2 Everyone
with some experience of deep-brain stimulation of the
subthalamic nucleus knows that neither the patient nor
the evaluator can be blinded to the status of a patient with
advanced Parkinsons disease who has resumed stimulation
of the subthalamic nucleus after having been without stim-
ulation and medication for 12 hours. Since the authors
themselves have admitted this fact in a previous publica-
tion,2 one cannot help but wonder about the validity of
this double-blind evaluation.
PATRIC BLOMSTEDT, M.D.
University Hospital
901 85 Ume, Sweden
patric_blomstedt@hotmail.com
1. The Deep-Brain Stimulation for Parkinsons Disease Study Group. Deep-
brain stimulation of the subthalamic nucleus or the pars interna of the globus
pallidus in Parkinsons disease. N Engl J Med 2001;345:956-63.
2. Kumar R, Lozano AM, Kim YJ, et al. Double-blind evaluation of sub-
thalamic nucleus deep brain stimulation in advanced Parkinsons disease.
Neurology 1998;51:850-5.
To the Editor: The article on deep-brain stimulation for
Parkinsons disease included a comprehensive listing of ad-
verse events associated with subthalamic and pallidal stim-
452 N Engl J Med, Vol. 346, No. 6 February 7, 2002 www.nejm.org
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Copyright 2002 Massachusetts Medical Society. All rights reserved.
ulation. Preliminary results of the same study were pre-
sented at the Movement Disorder Society meeting in New
York in October 1998. Obeso reported on the adverse
events associated with deep-brain stimulation of the sub-
thalamic nucleus in 36 patients, 33 of whom had bilateral
implants, and concluded that the risk cannot be minimized
but that the benefit is substantial.1 Lang presented the ad-
verse events associated with deep-brain stimulation of the
pallidum in 36 patients, 25 of whom had bilateral im-
plants, and concluded that complications were not uncom-
mon but that the riskbenefit ratio was quite acceptable.2
We are concerned about apparent major inconsistencies in
the reported number of side effects in the 1998 report and
the current report. In 1998 eight centers were involved in the
study of deep-brain stimulation of the subthalamic nucleus,
and six centers were involved in the pallidal deep-brain stim-
ulation study.1,2 The current report lists 18 centers. None-
theless, the number of some of the listed complications de-
creased between 1998 and 2001. To cite but one example,
4 of 36 patients who received deep-brain stimulation of the
subthalamic nucleus had dysarthria in 1998, whereas none
of 102 such patients had dysarthria as reported in 2001.
Hypophonia is not even mentioned. Deep-brain stimula-
tion of the basal ganglia is an efficient treatment for Parkin-
sons disease, but this method may lose credibility if its side
effects are not properly accounted for.
MARWAN I. HARIZ, M.D., PH.D.
University Hospital
901 85 Ume, Sweden
marwan.hariz@neuro.umu.se
HARALD FODSTAD, M.D., PH.D.
New York Methodist Hospital
Brooklyn, NY 11215
1. Obeso JA. Deep brain stimulation (DBS) of the subthalamic nucleus
(STN) in advanced Parkinsons disease (PD). Mov Disord 1998;13:Suppl
2:303. abstract.
2. Lang A. Deep brain stimulation (DBS) of the globus pallidus internus
(Gpi) in advanced Parkinsons disease (PD). Mov Disord 1998;13:Suppl 2:
264. abstract.
To the Editor: Although the study of deep-brain stimu-
lation for Parkinsons disease was described as a double-
blind, crossover, randomized study, this design pertains only
to the three-month evaluation. Blinding patient and investi-
gator to stimulation status is difficult, however, especially if
the patient has tremor or if the evaluations are performed
by the same investigator who programs the patients stim-
ulator settings. The key indications for deep-brain stimu-
lation in current practice are motor fluctuations and dys-
kinesias (off periods), variables not measured with the
use of a blinded evaluation.
Will deep-brain stimulation help the average patient
with Parkinsons disease, and if so, for how long? The 143
patients in the study were in their early 40s at the onset of
disease considerably younger than most patients with
Parkinsons disease. The analysis should have included all pa-
tients who underwent surgery, even those who had compli-
cations, reflecting the intention-to-treat principle inherent
in actual practice. To be able to generalize the results, read-
ers need to know whether the study group included all el-
 CORR ES POND ENCE
igible patients and patients who underwent the procedure
at each center during the enrollment period.
All who care for patients with Parkinsons disease recog-
nize the potential of deep-brain stimulation and hope that
its good effects will prove to be long lasting. But a true
test of this method requires a much longer follow-up than
three or six months.
BLAIR FORD, M.D.
Columbia University
New York, NY 10032-3784
The authors reply:
To the Editor: Blomstedt and Ford raise issues related to
blinding. We agree that when an intervention provides a
dramatic benefit, it has the potential to alert the patient or
evaluator to the treatment assignment. In the article quot-
ed by Blomstedt,1 patients were able to guess when their
stimulators were on almost entirely as a result of the pro-
found benefit associated with stimulation. Surely, when ef-
ficacy leads to the unblinding of a study, this outcome sup-
ports the extent of efficacy, rather than raises questions
about the validity of the observation. Stimulation can also
be associated with transient symptoms such as paresthesias
or motor twitch. However, neither the patients nor the
evaluators in our study were informed about or could be
certain of the patients stimulation status hence, the ad-
vantage of double-blind trials.
We agree that the effect of the intervention on off
time and dyskinesia are important variables. These are bet-
ter assessed in long-term, parallel-group, double-blind stud-
ies, which are presently under way. Nonetheless, patients in
our study who were markedly disabled and whose condition
could not be further improved by medical therapy obtained
substantial benefits from deep-brain stimulation with regard
to off time and dyskinesia. It is hard to imagine that this
benefit was entirely due to a placebo effect.
We included all patients who underwent or who were
intended to undergo bilateral procedures. We analyzed data
from all patients who participated in the crossover study and
from all visits completed. We enrolled patients who were rel-
atively young when they became ill, because these patients
have the most profound disability from motor complications
and are the most likely to benefit from this surgery.
Hariz and Fodstad fear that we did not account for all
adverse events. During the study, patients and physicians
were asked to record all adverse events in an open-ended
fashion. This information was duly collected and reported
to regulatory agencies. As stated in our article, we reported
only adverse events that were serious, that were severe and
were attributed to the intervention, or that affected more
than one patient. Because of space limitations, we did not
report mild, transient, and clinically insignificant adverse
events, such as those associated with the initiation of stim-
ulation. Our preliminary reports were presented in non
peer-reviewed abstract form2,3 and included some patients
from the current study as well as patients who underwent
unilateral procedures and who were not included in the
study. In these reports, we used different criteria for report-
ing adverse events, and the adverse events were reported be-
fore we had thoroughly reviewed the data base and uniform-
N Engl J Med, Vol. 346, No. 6 February 7, 2002 www.nejm.org 453
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Copyright 2002 Massachusetts Medical Society. All rights reserved.
ly classified and confirmed adverse events. We agree that
the side effects of a new procedure must be carefully
documented, and we took great pains to ensure that this
was done.
JOSE A. OBESO, M.D.
University of Navarra
Pamplona 31008, Spain
C. WARREN OLANOW, M.D.
Mount Sinai School of Medicine
New York, NY 10029
warren.olanow@mssm.edu
ANTHONY LANG, M.D.
University of Toronto
Toronto, ON M5T 2S8, Canada
1. Kumar R, Lozano AM, Kim YJ, et al. Double-blind evaluation of sub-
thalamic nucleus deep brain stimulation in advanced Parkinsons disease.
Neurology 1998;51:850-5.
2. Obeso JA. Deep brain stimulation (DBS) of the subthalamic nucleus
(STN) in advanced Parkinsons disease (PD). Mov Disord 1998;13:Suppl
2:303. abstract.
3. Lang A. Deep brain stimulation (DBS) of the globus pallidus internus
(Gpi) in advanced Parkinsons disease (PD). Mov Disord 1998;13:Suppl 2:
264. abstract.
B-Type Natriuretic Peptide and Acute Coronary
Syndromes
To the Editor: In their interesting study of the prognostic
value of brain (B-type) natriuretic peptide in patients with
acute coronary syndromes, de Lemos et al. (Oct. 4 issue)1
did not thoroughly assess the possible confounding effect
of a well-established prognostic marker, C-reactive protein.
The authors state that 2525 patients provided plasma sam-
ples for the measurement of B-type natriuretic peptide and
that C-reactive protein was also measured in 925 of these
patients. The authors report that the univariate analysis
showed only a moderately strong association between the
level of B-type natriuretic peptide and the level of C-reac-
tive protein (r=0.2, P<0.001). They later affirm that B-type
natriuretic peptide remained a significant independent
prognostic factor in a multivariate logistic-regression analy-
sis adjusted for several other independent predictors, in-
cluding troponin I levels and ST-segment deviation. How-
ever, the multivariate analysis did not evaluate the possible
role of C-reactive protein in the outcome-prediction
model.
The important and independent role of C-reactive pro-
tein as a prognostic factor in patients with acute coronary
syndromes, in both the short term and the long term, is now
well established.2-5 We therefore believe that a thorough
multivariate analysis of the 925 patients for whom data
were available on both C-reactive protein and B-type na-
triuretic peptide levels could provide important informa-
tion about the pathophysiological and clinical implications
of neurohormonal activation and inflammation in unstable
coronary syndromes, as well as defining the incremental
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
role of B-type natriuretic peptide independently from the
roles of the other available markers.
GIUSEPPE G.L. BIONDI-ZOCCAI, M.D.
ANTONIO ABBATE, M.D.
LUIGI M. BIASUCCI, M.D.
Catholic University of the Sacred Heart
00168 Rome, Italy
gbiondizoccai@tiscalinet.it
1. de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of
B-type natriuretic peptide in patients with acute coronary syndromes.
N Engl J Med 2001;345:1014-21.
2. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of
C-reactive protein and serum amyloid A protein in severe unstable angina.
N Engl J Med 1994;331:417-24.
3. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive
protein at discharge in patients with unstable angina predict recurrent in-
stability. Circulation 1999;99:855-60.
4. Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent
predictor of mortality independently of and in combination with troponin
T in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol
1998;31:1460-5.
5. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of my-
ocardial damage and inflammation in relation to long-term mortality in un-
stable coronary artery disease. N Engl J Med 2000;343:1139-47.
To the Editor: Although the study by de Lemos and col-
leagues has important clinical implications, several points
are worth highlighting. The authors state that patients with
higher B-type natriuretic peptide levels had a greater num-
ber of stenosed coronary arteries than did patients with
lower levels of the peptide, but they do not present data on
the affected vessels. These data are relevant, since a previous
study of B-type natriuretic peptide showed that patients
with right coronary artery disease have both a lower plasma
level at rest and a smaller increase in the level after exercise
than do patients with left coronary artery disease.1 Higher
levels of B-type natriuretic peptide may identify patients
with left coronary artery disease in particular, left anteri-
or descending coronary artery disease and this may ex-
plain the link between the peptide level and the prognosis.
The authors propose that a threshold of 80 pg per milliliter
is an appropriate predictor of survival for patients with acute
coronary syndromes. However, this level is derived from stud-
ies of heart failure. The optimal cutoff point may be lower
in patients with acute coronary syndromes than in those with
heart failure, since in the latter group, B-type natriuretic pep-
tide levels are higher. Formal evaluation with the use of receiv-
er-operating-characteristic curves to determine the optimal
threshold for prognosis would have been more informative.
The investigators chose to evaluate a group of patients
who went on to receive active treatment rather than place-
bo. A study of the placebo group might have been more
valid, since the trial was terminated prematurely because
of increased mortality in the active-treatment group.2
PAUL R. KALRA, M.R.C.P.
RAKESH SHARMA, M.R.C.P.
National Heart and Lung Institute
London SW3 6LY, United Kingdom
p.kalra@ic.ac.uk
ALLAN D. STRUTHERS, M.D., F.R.C.P.
Ninewells Hospital
Dundee DD1 9SY, United Kingdom
454 N Engl J Med, Vol. 346, No. 6 February 7, 2002 www.nejm.org
The New England Journal of Medicine
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Copyright 2002 Massachusetts Medical Society. All rights reserved.
1. Davidson NC, Pringle SD, Pringle TH, McNeill GP, Struthers AD.
Right coronary artery stenosis is associated with impaired cardiac endo-
crine function during exercise. Eur Heart J 1997;18:1749-54.
2. Cannon CP, McCabe CH, Wilcox RG, et al. Oral glycoprotein IIb/IIIa
inhibition with orbofiban in patients with unstable coronary syndromes
(OPUS-TIMI 16) trial. Circulation 2000;102:149-56.
The authors reply:
To the Editor: Biondi-Zoccai and colleagues state that
C-reactive protein may have had a confounding effect on
the association between B-type natriuretic peptide and
mortality. Our multivariate model included only variables
that could be evaluated in at least 75 percent of the pa-
tients.1 Because C-reactive protein was measured in only
925 of 2525 patients, it was not included in this model.
However, when C-reactive protein was forced into an
identical multivariate model that was limited to the 835
patients for whom complete data were available for all var-
iables, including C-reactive protein, B-type natriuretic
peptide remained an independent predictor of mortality at
10 months. The adjusted odds ratios for mortality at 10
months among patients with B-type natriuretic peptide
levels in the second, third, and fourth quartiles (as com-
pared with the first quartile) were 5.0 (95 percent confi-
dence interval, 1.4 to 18.0), 4.0 (95 percent confidence in-
terval, 1.1 to 14.1), and 6.0 (95 percent confidence
interval, 1.8 to 20.4), respectively.
Kalra and colleagues raise three points. First, they note
that B-type natriuretic peptide levels may be higher in
patients with right-coronary-artery stenoses than in
those with left-coronary-artery stenoses.1 This suggestion
is plausible, since a larger myocardial territory is subtended
by the left coronary artery, and a relation exists between
the degree of ischemia and the magnitude of the elevation
in the level of B-type natriuretic peptide.2 However,
among the 1239 patients in our study for whom angio-
graphic data were available, the B-type natriuretic peptide
level was similar regardless of whether the culprit lesion
was in the left anterior descending artery (115139 pg
per milliliter), the circumflex artery (10097 pg per mil-
liliter), or the right coronary artery (108120 pg per mil-
liliter).
Second, the authors ask whether a threshold lower
than 80 pg per milliliter would be more appropriate for
prognostic assessment in patients with acute coronary syn-
dromes. We prospectively selected the threshold of 80 pg
per milliliter to enhance the generalizability of our find-
ings. Lower thresholds, evaluated retrospectively, do not
appear to improve the overall predictive value as reflected
by the chi-square test. Given the graded relation between
the level of B-type natriuretic peptide and mortality in
our analysis according to quartiles,3 a dichotomous thresh-
old may not be the optimal approach to clinical appli-
cation.
Finally, the authors suggest that it might have been
more valid to study a placebo group rather than an active-
treatment group. In the Oral Glycoprotein IIb/IIIa Inhi-
bition with Orbofiban in Patients with Unstable Coronary
SyndromesThrombolysis in Myocardial Infarction 16 tri-
al, only one of the two active-treatment groups had excess
mortality.4 In our study, we used only blood samples from
 C ORR ES POND ENCE
the group of patients who received 50 mg of orbofiban for
the duration of the study.3 Mortality in this group did not
exceed that in the placebo group.4
JAMES A. DE LEMOS, M.D.
University of Texas Southwestern Medical Center
Dallas, TX 75390-9034
james.delemos@utsouthwestern.edu
DAVID A. MORROW, M.D., M.P.H.
EUGENE BRAUNWALD, M.D.
Brigham and Womens Hospital
Boston, MA 02115
1. de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of
B-type natriuretic peptide in patients with acute coronary syndromes.
N Engl J Med 2001;345:1014-21.
2. Davidson NC, Pringle SD, Pringle TH, McNeill GP, Struthers AD.
Right coronary artery stenosis is associated with impaired cardiac endo-
crine function during exercise. Eur Heart J 1997;18:1749-54.
3. Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial and
brain natriuretic peptides during acute myocardial ischaemia induced by
dynamic exercise in patients with angina pectoris. Clin Sci (Lond) 1995;
88:551-6.
4. Cannon CP, McCabe CH, Wilcox RG, et al. Oral glycoprotein IIb/IIIa
inhibition with orbofiban in patients with unstable coronary syndromes
(OPUS-TIMI 16) trial. Circulation 2000;102:149-56.
Selective Postoperative Inhibition
of Gastrointestinal Opioid Receptors
To the Editor: In their article on prophylaxis against
postoperative ileus with the use of ADL 8-2698, Taguchi
et al. (Sept. 27 issue)1 refer to our report on intravenous
methylnaltrexone, a peripheral opioid antagonist.2 We call
attention to an error in their description of our study pop-
ulation. Our study did not involve patients with pain from
cancer but, rather, subjects receiving methadone-mainte-
nance therapy, who are exquisitely sensitive to the with-
drawal of opioids. The outcome measures thus included
the laxation response, oralcecal transit times, and symp-
toms of central opioid withdrawal.
All subjects in our treatment group had immediate lax-
ation, and none had symptoms of opioid withdrawal. We
have reported similar results with oral methylnaltrexone,
although evacuation was not immediate.3 The difference in
the time to evacuation may have been related to the route
of administration. Although ADL 8-2698 is clearly effective
as prophylaxis against ileus, a parenterally administered opi-
oid antagonist may be more useful for treatment, particu-
larly in patients undergoing gastric suction. Unlike ADL
8-2698, methylnaltrexone is formulated and effective both
orally and parenterally.
As Dr. Steinbrook suggests in the accompanying edito-
rial,4 there may be other therapeutic roles for peripheral opi-
oid antagonists. Nevertheless, their role in preventing post-
operative emesis remains unclear. The multifactorial nature
of postoperative emesis and the fact that opiates can both
induce and prevent emesis complicate the issue. The re-
sults of our study of methylnaltrexone in dogs for the pre-
vention of opioid-induced emesis were encouraging,5 but
neither we nor other investigators6 have found that methyl-
naltrexone significantly reduces postoperative vomiting in
N Engl J Med, Vol. 346, No. 6 February 7, 2002 www.nejm.org 455
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Copyright 2002 Massachusetts Medical Society. All rights reserved.
humans. However, methylnaltrexone reduces both the un-
desirable subjective effects and the pruritus associated with
opiate use.7
JONATHAN MOSS, M.D., PH.D.
CHUN-SU YUAN, M.D., PH.D.
University of Chicago
Chicago, IL 60637
jm47@airway2.uchicago.edu
Editors note: Drs. Moss and Yuan hold patent interests
in the use of methylnaltrexone.
1. Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhi-
bition of gastrointestinal opioid receptors. N Engl J Med 2001;345:935-
40.
2. Yuan CS, Foss JF, OConnor M, et al. Methylnaltrexone for reversal of
constipation due to chronic methadone use: a randomized controlled trial.
JAMA 2000;283:367-72.
3. Yuan CS, Foss JE. Oral methylnaltrexone for opioid-induced constipa-
tion. JAMA 2000;284:1383-4.
4. Steinbrook RA. An opioid antagonist for postoperative ileus. N Engl J
Med 2001;345:988-9.
5. Foss JF, Yuan CS, Roizen MF, Goldberg LI. Prevention of apomor-
phine- or cisplatin-induced emesis in the dog by a combination of methyl-
naltrexone and morphine. Cancer Chemother Pharmacol 1998;42:287-91.
6. Moerman I, Franck P, Camu F. Evaluation of methylnaltrexone for the
reduction of postoperative vomiting and nausea incidences. Acta Anaesthe-
siol Belg 1995;46:127-32.
7. Yuan CS, Foss JF, OConnor M, Osinski J, Roizen MF, Moss J. Efficacy
of orally administered methylnaltrexone in decreasing subjective effects af-
ter intravenous morphine. Drug Alcohol Depend 1998;52:161-5.
The editorialist replies:
To the Editor: Nausea and vomiting remain all too com-
mon after surgery. I agree with Moss and Yuan that post-
operative emesis is complex and probably multifactorial.
Although numerous pharmacologic approaches to prophy-
laxis and treatment for emesis have been recommended,1-3
opioid antagonists are not among them. Taguchi et al. re-
ported a substantial reduction in maximal nausea scores
and an absence of vomiting with the 6-mg dose of ADL
8-2698. Additional studies are warranted to define the role
of opioid antagonists in the prevention and management
of postoperative nausea and vomiting.
RICHARD A. STEINBROOK, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
1. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology,
treatment, and prevention. Anesthesiology 1992;77:162-84.
2. ASHP therapeutic guidelines on the pharmacologic management of
nausea and vomiting in adult and pediatric patients receiving chemotherapy
or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999;
56:729-64.
3. Scuderi PE, James RL, Harris L, Mims GR III. Multimodal antiemetic
management prevents early postoperative vomiting after outpatient lap-
aroscopy. Anesth Analg 2000;91:1408-14.
Withholding Proven Treatment in Research
To the Editor: In their editorial (Sept. 20 issue),1 Huston
and Peterson discuss developments in the debate about
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
withholding proven treatment in clinical research. Unfor-
tunately, the editorialists, citing the transcript of a televi-
sion report in which plaintiffs in a pending lawsuit described
their allegations, do not accurately describe the clinical re-
search on schizophrenia that was conducted at the Univer-
sity of California, Los Angeles (UCLA). In the UCLA
study,2 which was conducted between 1982 and 1993, pa-
tients consented to discontinue medication only after clin-
ical stabilization had been achieved, and they were moni-
tored closely. Offering patients with stabilized illness a
trial period without medication in the initial course of ill-
ness was within the standard of care and did not constitute
a withholding of proven treatment. In response to com-
plaints in 1991 by two families that filed lawsuits, the Office
for Protection from Research Risks found that the clinical
treatment of the patients adhered to currently accepted
clinical standards.3 Moreover, the unfortunate suicide of
one patient with schizophrenia occurred nearly three years
after his participation in the study had concluded.
KEITH H. NUECHTERLEIN, PH.D.
University of California, Los Angeles
Los Angeles, CA 90024-6968
keithn@ucla.edu
1. Huston P, Peterson R. Withholding proven treatment in clinical re-
search. N Engl J Med 2001;345:912-4.
2. Gitlin M, Nuechterlein K, Subotnik KL, et al. Clinical outcome follow-
ing neuroleptic discontinuation in patients with remitted recent-onset
schizophrenia. Am J Psychiatry 2001;158:1835-42.
3. Office for Protection from Research Risks. Evaluation of human subject
protections in schizophrenia research conducted by the University of Cal-
ifornia, Los Angeles. Rockville, Md.: National Institutes of Health, May 11,
1994.
The editorialists reply:
To the Editor: We illustrated the concern regarding the
withholding of proven treatment during the washout
phase of a trial by reference to a treatment trial for schizo-
phrenia that is now the focus of an ongoing legal case.1 We
described the allegations only; direct causality cannot be
assumed.
PATRICIA HUSTON, M.D., M.P.H.
ROBERT PETERSON, M.D., PH.D.
Health Canada
Ottawa, ON K1A 1B9, Canada
1. Superior Court of the State of California, for the County of Los Ange-
les, Case No. SC015698 (Aller) consolidated with Case No. SC016260
(Lamadrid).
Spironolactone and ACE Inhibition in Chronic
Renal Failure
To the Editor: I am surprised that the authors of the let-
ter entitled Spironolactone in Addition to ACE Inhibi-
tion to Reduce Proteinuria in Patients with Chronic Renal
Disease (Sept. 20 issue)1 concluded that the reduction in
proteinuria seen after the administration of 25 mg of spiro-
456 N Engl J Med, Vol. 346, No. 6 February 7, 2002 www.nejm.org
The New England Journal of Medicine
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Copyright 2002 Massachusetts Medical Society. All rights reserved.
nolactone per day could not be explained by an effect of
blood pressure, since there was no significant difference in
blood pressure before and after the administration of spi-
ronolactone.
In each of their eight patients, the mean blood pressure
(calculated as systolic pressure+[0.67diastolic pressure])
was lower after treatment than before treatment, the mean
(SE) change being 101.76 mm Hg. It is well estab-
lished that a reduction in mean blood pressure can pro-
duce a reduction in proteinuria.
The authors thesis would have been more convincing if
they had shown that proteinuria increased when spirono-
lactone was discontinued without any accompanying change
in arterial pressure.
FRANKLIN H. EPSTEIN, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
fepstein@caregroup.harvard.edu
1. Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibi-
tion to reduce proteinuria in patients with chronic renal disease. N Engl J
Med 2001;345:925-6.
To the Editor: In considering the beneficial effects of
spironolactone and angiotensin-convertingenzyme (ACE)
inhibition on proteinuria in patients with chronic renal
disease, it is important to examine the effects on serum
potassium levels. Although the risk of hyperkalemia in pa-
tients with chronic renal failure is low until the glomerular
filtration rate is less than 5 ml per minute, there is a group
of patients in whom hyperkalemia can develop before re-
nal failure is so advanced; this group includes the growing
population of patients with diabetes and hyporeninemic
hypoaldosteronism. The hyperglycemia that is common
among such patients and the salt restriction that is typical-
ly recommended to them can also predispose them to hy-
perkalemia.
We are afraid that the problem would grow if these treat-
ment recommendations were extended to patients with
chronic renal disease, even if the intention were to reduce
proteinuria. We wish to emphasize the importance of close
monitoring of serum potassium levels in these patients.
JAUME ALMIRALL, M.D.
THAS LOPEZ, M.D.
Corporaci Parc Taul
08208 Sabadell, Barcelona, Spain
jalmirall@cspt.es
The authors reply:
To the Editor: We thank Dr. Epstein for pointing out the
difference in mean blood pressure, which, unfortunately, we
had not calculated. Certainly we would not have expected
spironolactone to be such an effective antihypertensive
agent, but we acknowledge that its effect on blood pres-
sure could have contributed to its antiproteinuric effect. In
a meta-analysis of the effect of blood-pressurelowering
agents on proteinuria (41 studies, 1124 patients), Gan-
 C ORR ES POND ENCE
sevoort et al.1 reported that a similar decrease in mean
blood pressure (11.4 percent) was associated with a reduc-
tion of 17 percent in proteinuria if agents other than ACE
inhibitors were given, whereas ACE inhibitors (leading to a
12 percent reduction in blood pressure) resulted in a 39.9
percent reduction in proteinuria, suggesting that there is
a specific blood-pressureindependent effect of interfering
with the reninangiotensinaldosterone pathway. In future
studies of the effect of aldosterone antagonism on protein-
uria, specific attention will have to be paid to the effect on
the reninangiotensinaldosterone pathways and blood
pressure.
We also appreciate the comments from Drs. Almirall
and Lopez. In our group of patients, the serum potassium
level did rise after the addition of spironolactone, but it re-
mained in the normal range. This finding is consistent with
those of the Randomized Aldactone Evaluation Study.2
Although patients with diabetes may have hyporeninemic
hypoaldosteronism, it is not known whether the presence of
this condition would militate against the therapeutic ben-
efit of aldosterone-receptor blockade. Until recently, it has
been believed that the adrenal cortex was the only site of
mineralocorticoid production. Studies indicate that aldos-
terone synthesis occurs at extrarenal sites, including the en-
dothelium and smooth-muscle cells.3 There is also evidence
that the aldosterone response can be dissociated from cir-
culating aldosterone levels.4,5 We agree that spironolactone
should only be added to ACE inhibitor therapy with great
caution in patients with renal impairment, since there is a
risk of hyperkalemia that may be exacerbated by concom-
itant hyporeninemic hypoaldosteronism.
ANASTASIA CHRYSOSTOMOU, B.M., B.S.
GAVIN BECKER, M.D., M.B., B.S.
Royal Melbourne Hospital
Parkville 3052, Australia
anastasiac@optusnet.com.au
1. Gansevoort RT, Sluiter WJ, Hemmelder MH, de Zeeuw D, de Jong PE.
Antiproteinuric effect of blood-pressure-lowering agents: a meta-analysis of
comparative trials. Nephrol Dial Transplant 1995;10:1963-74.
2. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure. N Engl J Med
1999;341:709-17.
3. Hatakeyama H, Miyamori I, Fujita T, Takeda Y, Takeda R, Yamamoto
H. Vascular aldosterone: biosynthesis and a link to angiotensin II-induced
hypertrophy of vascular smooth muscle cells. J Biol Chem 1994;269:
24316-20.
4. Takeda Y, Miyamori I, Inaba S, et al. Vascular aldosterone in genetically
hypertensive rats. Hypertension 1997;29:45-8.
5. Brown NJ, Nakamura S, Ma L, et al. Aldosterone modulates plasmino-
gen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 2000;
58:1219-27.
N Engl J Med, Vol. 346, No. 6 February 7, 2002 www.nejm.org 457
The New England Journal of Medicine
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Tranexamic Acid in Hereditary Hemorrhagic
Telangiectasia
To the Editor: Sabb et al. (Sept. 20 issue)1 report the ef-
ficacy of tranexamic acid in reducing epistaxis in hereditary
hemorrhagic telangiectasia. However, the title of their com-
munication may be misleading. The authors do not men-
tion the weight of the three patients they describe, an omis-
sion that hinders the evaluation of the doses administered.
The total doses of tranexamic acid given to the three pa-
tients (4.0, 4.0, and 4.5 g per day), in contrast to the un-
usually high doses suggested by the title, correspond to
the usual dose recommended for an average adult weigh-
ing 70 kg: 15 to 25 mg per kilogram of body weight three
or four times daily.2,3
MIGUEL LOZANO, M.D., PH.D.
Hospital Clnic Barcelona
08036 Barcelona, Spain
mlozano@clinic.ub.es
1. Sabb C, Gallitelli M, Palasciano G. Efficacy of unusually high doses of
tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic tel-
angiectasia. N Engl J Med 2001;345:926.
2. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs
1985;29:236-61.
3. Raasch RH. Tranexamic acid (Drug Consult). In: Hutchinson TA, Sha-
han DR, eds. Drugdex System. Greenwood Village, Colo.: Micromedex,
Inc. (Edition expires 3/2002.)
The authors reply:
To the Editor: In Italy, information in the package insert
for tranexamic acid suggests that an oral dose of 1.0 to 3.0 g
daily is therapeutic; we gave our patients 4.0 to 4.5 g daily,
doses that we considered high. Moreover, the references
cited by Lozano concern epistaxis of unexplained origin,
whereas we reported the use of tranexamic acid in patients
with hereditary hemorrhagic telangiectasia.
CARLO SABB, M.D.
MAURO GALLITELLI, M.D.
NICOLA CIAVARELLA, M.D.
Policlinico di Bari
70124 Bari, Italy
c.sabba@dimimp.uniba.it
Correspondence Copyright 2002 Massachusetts Medical Society.