Pla.ce.bo.free.fr

When Are Medication Side Effects
evaluation of tricyclic antidepressants, atropine can be used in Due to the Nocebo Phenomenon?
the control group to mimic side effects, thus decreasing thelikelihood that either investigators or subjects would infer the To the Editor: In their discussion of the nocebo phenom-
correct treatment assignment. Indeed, there are indications enon, Dr Barsky and colleagues1 do not adequately address the that the difference in effectiveness between active drug and issue of causality. Like the distinction between “adverse events” placebo is markedly less when an active drug is compared (which occur while receiving a drug, irrespective of causality) with an active placebo.4 Thus, recent reviews have empha- and “adverse drug reactions” (which have a plausible causal sized the importance of an active placebo control group in relationship to the drug), any discussion of the nocebo phe- drug efficacy trials, due to their superior capacity to maintain nomenon should distinguish between adverse events occur- ring while receiving placebo vs those directly attributable to Finally, direct evaluation of drug effects, expectancy ef- it. In the studies that Barsky et al cite as offering quantitative fects, and their interactions can best be obtained by the bal- support for their position, it is not clear that this distinction anced placebo design, which yields a 2 ϫ2 matrix comprising has been made, since most clinical trials elicit adverse events 4 conditions in which subjects are (1) told they will get a drug by asking questions such as “Have you felt differently in any and receive the drug, (2) told they will get a drug but receive way since your last visit?” Because it is even more difficult to placebo, (3) told they will not get a drug but receive the drug determine causality for placebos than for active drugs, it will in disguised form, and (4) told they will not get a drug and be challenging to obtain accurate information on the magni- receive no drug.5 I recommend that this design be used more often in clinical trials of efficacy evaluation.
Robert H. Palmer, MD
Opher Caspi, MD, MA
Forest Laboratories, Inc
Program in Integrative Medicine
New York, NY
University of Arizona
Tucson
1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side ef-
fects and the nocebo phenomenon. JAMA. 2002;287:622-627.
1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side ef-
fects and the nocebo phenomenon. JAMA. 2002;287:622-627.
2.
To the Editor: I would like to add 3 clarifications to the
Hahn RA. The nocebo phenomenon: concept, evidence, and implications for public health. Prev Med. 1997;26:607-611.
article by Dr Barsky and colleagues on nonspecific medication 3. Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H. The role of expect-
side effects and the nocebo phenomenon.1 First, following the ancies in the placebo effect and their use in the delivery of health care: a system-atic review. Health Technol Assess. 1999;3:1-96.
model suggested by Hahn,2 a distinction must be made 4. Salamone JD. A critique of recent studies on placebo effects of antidepres-
between the nocebo phenomenon and placebo side effects.
sants: importance of research on active placebos. Psychopharmacology. 2000;152:1-6.
According to Hahn, the nocebo hypothesis proposes that 5. Kirsch I, Weixel LJ. Double-blind versus deceptive administration of a placebo.
expectations of sickness and the affective states associated Behav Neurosci. 1988;102:319-323.
with such expectations cause such symptoms in patients whoexpect them. Placebo side effects, on the other hand, occur To the Editor: Dr Barsky and colleagues1 discuss mecha-
when expectations of healing produce sickness; that is, when nisms by which patients who receive placebos may report ad- a positive expectation has a negative outcome. Likewise, verse effects (the “nocebo phenomenon”). While they iden- nocebos may also have side effects; that is, when negative tify several important factors, such as misattribution of expectations produce positive outcomes or outcomes other temporally coincident symptoms and perhaps conditioning, they than those expected. This distinction is not just a matter of do not consider that placebo ingredients may produce symp- semantics. I suspect that much of what is labeled as the“nocebo phenomenon” represents, in fact, placebo side GUIDELINES FOR LETTERS. Letters discussing a recent JAMA article should
effects. In patients who somaticize and in those who are dif- be received within 4 weeks of the article’s publication and should not exceed 400 fusely pessimistic, distinguishing between the 2 concepts words of text and 5 references. Letters reporting original research should not ex-ceed 500 words and 6 references. All letters should include a word count. Letters admittedly may be difficult. The key is that expectations play must not duplicate other material published or submitted for publication. Letters a causal role in health and healing as well as in sickness.3 will be published at the discretion of the editors as space permits and are subjectto editing and abridgment. A signed statement for authorship criteria and respon- Second, the assertion that in clinical trials placebo side sibility, financial disclosure, copyright transfer, and acknowledgment is required effects “ . . . could reduce the treatment effect”1 needs more for publication. Letters not meeting these specifications are generally not consid- elucidation. Not all placebos are alike. Whereas the most ered. Letters will not be returned unless specifically requested. Also see Instruc-tions for Authors ( January 2, 2002). Letters may be submitted by surface mail: common form of placebo is inactive, other placebos are Letters Editor, JAMA, 515 N State St, Chicago, IL 60610; e-mail: JAMA-letters@ama active, that is, they produce detectable side effects without -assn.org; or fax (please also send a hard copy via surface mail): (312) 464-5225.
any therapeutic effects. For example, in the double-blind Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.
2502 JAMA, May 15, 2002—Vol 287, No. 19 (Reprinted)
2002 American Medical Association. All rights reserved.
toms. There are no regulations dictating what constitutes a pla- suggestion of a collaborative strategy to treat anxious, de- cebo; placebo constituents are seldom reported, precluding ac- pressed, or somatizing patients. Depressed patients with el- countability and input regarding effects of these constituents, evated anxiety and somatic symptoms receiving usual care for and there is no foundation for the assumption that any pla- depression have been found to adhere well to antidepressant cebo constituent is truly physiologically inert.2-4 therapy, and their anxiety and somatization improve with treat- Even substances that are not absorbed can have effects.
Sugar pills may affect blood insulin levels with their cascade In their list of psychological characteristics associated with of physiological effects, and a lactose “placebo” reportedly side effects, I believe that Barsky et al missed 2 characteristics— led to increased dropout rates in the control group in a study health concerns and conversion—that have been shown to also of patients with the human immunodeficiency virus, who predict the important clinical outcome of nonadherence in de- have high rates of lactose (and sucrose) intolerance5; simi- pressed primary care patients.3 Depressed patients with el- larly, lactose placebos were a possible source of markedly evated levels of health concerns and conversion appear to in- increased gastrointestinal side effects in the placebo group terpret side effects as worsening overall health status and are in a study of patients with cancer.6 Subjects may react to less likely to adhere to antidepressant therapy. The collabora- excipients, stabilizers, dyes, or other elements, and I have tive strategy and reattribution process outlined by Barsky et al cared for one patient whose painful unilateral neuropathy may be more appropriately applied to this subgroup of de- symptoms were ultimately traced—in repeated n-of-1 blinded pressed patients. Researchers investigating nonadherence, side comparison—to magnesium stearate, a common lubricant in effects, and the nocebo effect may want to incorporate psycho- metric instruments measuring health concerns and conver- Apparent positive, negative, or neutral effects of an active sion along with the more common measures for somatization, drug could be spurious consequences of a negative, positive, or same direction results of a placebo, and there are cases in Robert Keeley, MD
which such effects appear to have occurred.2 Inconsistent find- Department of Family Medicine
ings across studies could result, in some instances, from dif- University of Colorado Health Sciences Center
ferences in the agent to which the active drug is compared. But even if placebo constituents have no impact on the primary out-come being studied, the assumption that they can have no effect 1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side ef-
on adverse symptoms is unsupportable.
fects and the nocebo phenomenon. JAMA. 2002;287:622-627.
2. Kroenke K, West SL, Swindle R, et al. Similar effectiveness of paroxetine, fluox-
Thus, physiological effects of the placebo ingredients—in ad- etine, and sertraline in primary care: a randomized trial. JAMA.2001;286:2947- dition to factors like misattribution or perhaps suggestibility— 2955.
3. Keeley R, Smith M, Miller J. Somatoform symptoms and treatment nonadher-
may influence nocebo effects. Because the manufacture of pla- ence in depressed family medicine outpatients. Arch Fam Med. 2000;9:46-54.
cebos and designation of their composition are often determinedby the companies that manufacture the drug under study, and In Reply: These letters underscore how complex and compli-
because the composition is typically unreported, there is po- cated a topic the nocebo phenomenon is and how important tential for conflict of interest in selection of ingredients. For precise terminology becomes. We agree with Dr Palmer that many reasons, then, the full disclosure of both placebo and ac- “adverse events” are distinct from “side effects” and not all ad- tive drug preparations should be reported.
verse events are attributable to the placebo or to the drug. In Beatrice Golomb, MD, PhD
clinical practice, however, this distinction may be all but im- Department of Medicine
possible to make. This is why we defined “side effects” as any University of California, San Diego, School of Medicine
unintended adverse symptom that the patient attributed to the drug. Several of these letters refer to the role of expectancy inthe occurrence of side effects, and Dr Caspi accurately points 1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side ef-
fects and the nocebo phenomenon. JAMA. 2002;287:622-627.
out that the term “nocebo” most properly refers to symptoms 2. Golomb B. Paradox of placebo effect. Nature. 1995;375:530.
that occur when the suggestions, instructions, and/or expec- 3. Golomb BA. Are placebos bearing false witness? Chem Industry. 1995;21:
tations accompanying the placebo are negative, as exempli- 900.
4. Golomb BA. Using placebos. Nature. 1996;379:765.
fied by hexing and voodoo curses. This has been distin- 5. Corazza GR, Ginaldi L, Furia N, Marani-Toro G, Di Giammartino D, Quaglino
guished from “placebo side effects,” which occur when the D. The impact of HIV infection on lactose absorptive capacity. J Infect. 1997;35:31-35.
explicit intent and expectations accompanying the placebo are 6. Loprinzi CL, Ellison NM, Schaid DJ, et al. Controlled trial of megestrol acetate
positive and beneficial. In clinical practice, obviously, physi- for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst. 1990;82:1127-1132.
cians do not prescribe medication with harmful intent and there-fore it is only the patient’s negative expectations that are rel- To the Editor: Dr Barsky and colleagues1 observe that pa-
tients who somatize or who are anxious or depressed have bet- These letters also point out the complexities inherent in the ter recollection of side effects to antidepressant therapy. While placebo notion itself. Thus, Caspi notes that several types of I agree with this observation, there is little support for their placebo may be used in controlled trials. Although most pla- 2002 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 15, 2002—Vol 287, No. 19 2503
cebos are devoid of all pharmacological activity, a more so- 2. Todres ID, Catlin EA, Thiel MM, Kessler C. The intensivist in a spiritual care train-
ing program: a clinical pastoral education (CPE) fellowship. Crit Care Med. 2001;
phisticated variant is a placebo that produces symptoms re- sembling the side effect profile of the active drug it is being 3. Catlin EA, Guillemin JH, Thiel MM, Hammond S, Wang ML, O’Donnell J. Spiri-
compared with. Dr Golomb points out that even placebos as- tual and religious components of patient care in the neonatal intensive care unit:sacred themes in a secular setting. J Perinatol. 2001;21:426-430.
sumed to be chemically inert may actually have physiologicalactions that produce symptoms. We agree with her sugges- This letter was shown to Dr Lo, who declined to reply.—ED.
tion that the composition of the placebo used in each studyshould be reported explicitly.
Finally, as Dr Keeley notes, side effect reporting is related RESEARCH LETTERS
to the problem of nonadherence. We agree that the combina-tion of depression and elevated health concerns may be Frequency of Inappropriate
particularly likely to result in nonadherence to the therapeu- Metformin Prescriptions
Arthur J. Barsky, MD
To the Editor: Metformin is commonly used in the manage-
Malcolm P. Rogers, MD
ment of type 2 diabetes. More than 25 million prescriptions Jonathan F. Borus, MD
for metformin were written in 2000, making it the most com- Brigham and Women’s Hospital and Harvard Medical School
monly prescribed branded diabetes medication in the United Boston, Mass
States.1 Metformin has been associated with the developmentof lactic acidosis, and since its initial marketing in 1995 the Should Physicians Address
US Food and Drug Administration (FDA) has required a “black Patients’ Spiritual Needs?
box” warning in the package insert.2,3 Labeled contraindica-tions include renal dysfunction and congestive heart failure To the Editor: The article by Dr Lo and colleagues1 recom-
(CHF) requiring pharmacologic treatment.4 We sought to mends practical approaches for clinicians exploring the spiri- determine the frequency of metformin use in a sample of tual crises of gravely ill patients. We agree with Lo et al that patients with these 2 primary contraindications to therapy.
the roles of physician and pastoral counselor should be sepa- Methods. We performed a retrospective chart review of pa-
rate in the early stages of the relationship because patients and tients receiving metformin through our outpatient pharmacy their families may not be prepared initially to trust or under- at an academic medical center. Institutional review board ap- stand the role of such a fused figure. However, as the patient- proval was obtained, and all patients with 2 or more prescrip- physician relationship develops, we believe that it may be of tions for metformin processed between January 1, 2000, and value to both the patient and the caregivers for the physician September 30, 2000, were identified. These patient records were to explore the patient’s existential and spiritual concerns. For randomized using a random number generator (SAS v6.12, SAS physicians to attain the self-confidence to perform this func- tion, however, requires a deeper understanding of the issues The prevalence of inappropriate prescriptions for metfor- than can be provided by reading an article on practical guide- min was defined as the percent of patients receiving metfor- lines. Our experience in a clinical pastoral education program min who had documented CHF or renal dysfunction. Patients modified for clinicians2 provided us with the skills, language, were considered to have CHF if the diagnosis was included in and experience to carry out the valuable recommendations of the medical problem list or clinic notes, and if they were tak- ing medications for CHF (diuretics, angiotensin-converting en- Spiritual distress is also experienced by caregivers of criti- zyme inhibitors, digoxin). Renal dysfunction was defined as a cally ill patients. For example, in our neonatal intensive care serum creatinine greater than 1.5 mg/dL (132.6 µmol/L) for unit, only 4% of staff surveyed denied experiencing suffering men and greater than 1.4 mg/dL (123.8 µmol/L) for women.
in their work and 83% reported privately praying for their in- Patient records were also reviewed for documentation of func- fant patients.3 Many patients have expressed a wish to have their tional cardiac status or evidence that contraindications were spiritual and religious concerns addressed by the physician. It behooves the medical profession to respond in a constructive Results. Pharmacy records identified 241 patients with 2 or
way, recognizing both patients’ and physicians’ spiritual and more prescriptions for metformin; 100 of these were ran- domly selected for chart review. Twenty-two patients (22%; 95%confidence interval, 14%-30%) were found to have either CHF Elizabeth A. Catlin, MD
requiring medications or renal insufficiency. Of these 22 pa- I. David Todres, MD
Ethics and Spiritual Support Unit
tients, 14 had CHF only, 5 had renal insufficiency only, and 3 MassGeneral Hospital for Children
had both. For patients with contraindications to metformin, Boston, Mass
the mean age was 60 years, 50% were women, and 50% wereAfrican American. These characteristics were similar for pa- 1. Lo B, Ruston D, Kates LW, et al. Discussing religious and spiritual issues at the
end of life: a practical guide for physicians. JAMA. 2002;287:749-754.
tients without contraindications. Patients with contraindica- 2504 JAMA, May 15, 2002—Vol 287, No. 19 (Reprinted)
2002 American Medical Association. All rights reserved.
tions did have a significantly longer duration of diabetes (14.2 5. Holstein A, Nahrwold D, Hinze S, Egberts EH. Contra-indications to metformin
therapy are largely disregarded. Diabet Med. 1999;16:692-696.
6. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in pa-
Of the 17 patients with CHF, 4 patients had a documented tients with NIDDM. Diabetes Care. 1997;20:925-928.
New York Heart Association functional classification (class II: 7. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2 dia-
betes mellitus. Drug Saf. 1999;20:489-503.
n = 2; class III: n = 2). Of the 8 patients with renal dysfunction,the mean serum creatinine was 1.8 mg/dL (159.1 µmol/L) andmean blood urea nitrogen was 27 mg/dL (9.639 mmol/L). Only Skeletal Muscle Glucocorticoid Receptor Density
2 patients had documentation in the medical record that pro- and Insulin Resistance
viders considered metformin contraindications.
Comment. In our review, almost one quarter of patients
To the Editor: In Cushing syndrome, elevated plasma corti-
with a prescription for metformin had 1 or more absolute sol levels cause insulin resistance, hyperglycemia, hyperten- contraindications. Several recent studies in Europe have sion, and dyslipidemia. In patients without Cushing syn- documented similar rates of inappropriate metformin pre- drome, these cardiovascular risk factors are associated with more subtle elevations in plasma cortisol concentrations1 and en- Adverse event reports suggest the incidence of metformin- hanced tissue responsiveness to glucocorticoids.2 We ex- associated lactic acidosis is between 1 in 10 000 to 1 in 100 000 plored the possibility that insulin resistance in patients with- patient-years.7 In the first 14 months after its release in the United out Cushing syndrome involves dysregulation of glucocorticoid States, the FDA received 47 confirmed cases of lactic acidosis associated with metformin, with a 42% mortality rate. More Methods. We obtained biopsies of vastus lateralis skeletal
than 90% of patients had relative or absolute contraindica- muscle under local anesthesia from 23 men without fasting hy- perglycemia participating in the the Uppsala Longitudinal Study Because our assessment of the prevalence of contraindica- of Adult Men.3 As previously described, participants under- tions to metformin use relies on a chart review, it may under- went a 75-g oral glucose tolerance test, euglycemic hyperin- estimate the frequency of contraindications and it is difficult sulinemic clamp, and ambulatory blood pressure recording.
to determine whether clinicians are aware they are prescrib- Height, weight, and waist and hip circumferences were mea- ing metformin against a black-box warning. Nonetheless, our sured. Glucocorticoid receptor messenger RNA (mRNA) lev- results suggest that metformin frequently may be inappropri- els were measured in muscle total RNA using a quantitative ately prescribed despite black-box contraindications. Docu- reverse transcriptase (RT) polymerase chain reaction (PCR) as- mentation of this potential risk in the medical record is lim- say with synthetic RNA competitors for GR mRNA and 18S ited and health care providers should consider improving the mRNA as internal control. Both competitors contained 83 base documentation of the risk of lactic acidosis and provide ap- pair deletions to distinguish PCR products derived from en- propriate counseling for patients who receive the drug.
dogenous and synthetic RNAs.4 The interassay coefficient of Cheryl Horlen, PharmD
variation was 12%. Stata v5.0 (Stata Corp, College Station, Tex) School of Pharmacy
Campbell University
Results. Results are shown in the TABLE. After adjusting for
Buies Creek, NC
body mass index (BMI), higher levels of skeletal muscle GR Robb Malone, PharmD, CDE
mRNA were associated with hypertension, higher insulin lev- Betsy Bryant, PharmD, CDE
els after a glucose load, and insulin resistance in a euglycemic Department of Medicine
hyperinsulinemic clamp. Muscle GR mRNA was not associ- University of North Carolina
ated with plasma lipids, glucose, or BMI alone.
Chapel Hill
Comment. These data show that men with insulin resis-
Betty Dennis, PharmD, MS, CDE
University of North Carolina Hospital Pharmacy
tance and hypertension have increased GR mRNA levels Chapel Hill
and, by inference, increased numbers of GRs in skeletal Tim Carey, MD, MPH
muscle. Glucocorticoid receptors mediate diverse effects on Mike Pignone, MD, MPH
insulin sensitivity (in liver, adipose tissue, and skeletal Russell Rothman, MD, MPP
muscle) and blood pressure (in kidney, blood vessels, and Department of Medicine
brain). Increased numbers of receptors in these sites could University of North Carolina
contribute to the association between features of the insulin Chapel Hill
resistance syndrome, and explain enhanced responsiveness 1. Top 200 drugs by retail sales in 2000. Drug Topics 2001. March 19, 2001.
to glucocorticoids.2 Glucocorticoid receptors also contribute 2. Emslie-Smith AM, Boyle DI, Evans JM, Sullivan F, Morris AD. Contraindica-
to negative feedback regulation of the hypothalamic- tions to metformin therapy in patients with Type 2 diabetes: a population-basedstudy of adherence to prescribing guidelines. Diabet Med. 2001;18:483-488.
pituitary-adrenal axis. If receptor expression were similarly 3. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic aci-
increased in central feedback sites, it might be expected that dosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338: lower circulating cortisol levels would compensate for 265-266.
4. Glucophage. Princeton, NJ: Bristol-Myers Squibb; 2001.
2002 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 15, 2002—Vol 287, No. 19 2505
Table. Associations of GR mRNA Levels With Cardiovascular Risk Factors*
Risk Factor
Mean (SD)
Partial Correlation Coefficient†
P Value
P Value Adjusted for BMI
Insulin sensitivity as M/I (mg·min−1·kg−1[mU/1]−1)࿣ *GR indicates glucocorticoid receptor; mRNA, messenger RNA; BMI, body mass index; and NA, not applicable.
†All associations with GRs are adjusted for 18s mRNA.
‡Median and interquartile range are presented, but variables were loge transformed for statistical comparisons.
§To convert mean (SD) glucose values to mM, multiply by 0.0555; to convert insulin values to pM, multiply by 6.945; to convert triglyceride values to mM, multiply by 0.0113.
࿣M/I = glucose infusion rate (g·min−1) between 60 and 120 minutes of the euglycemic clamp divided by body weight (kg) and mean insulin level (mU·1−1).
¶Associations with 24-hour mean ambulatory blood pressure were examined by censored normal regression to discount the effect of antihypertensive therapy. The 6 men receiving antihypertensive therapy and the 3 with untreated values above 150 mm Hg were allocated to the top tertile; median is presented and no partial correlation coefficient can becalculated.
However, dysregulation of GR expression appears to be tissue- Hans O. Lithell, PhD
specific. In an animal model of insulin resistance, dysregula- Department of Geriatrics
tion of GR expression was associated with increased GR mRNA Uppsala University
Uppsala, Sweden
in the liver but decreased GR mRNA in central negative feed-back sites.5 Further understanding of tissue-specific varia-tions in GR expression and function may offer fundamental in- Acknowledgment: Dr Reynolds is a Wellcome Trust Cardiovascular Research
sights into the pathophysiology of insulin resistance and its Initiative Clinical Training Fellow. Dr Walker is a British Heart Foundation Senior Rebecca M. Reynolds, MRCP
1. Phillips DIW, Walker BR, Reynolds RM, et al. Low birthweight and elevated
Karen E. Chapman, PhD
plasma cortisol concentrations in adults from three populations. Hypertension. 2000;35:1301-1306.
Jonathan R. Seckl, PhD
2. Walker BR, Phillips DIW, Noon JP, et al. Increased glucocorticoid activity in men
Brian R. Walker, MD
with cardiovascular risk factors. Hypertension. 1998;31:891-895.
Molecular Medicine Centre
3. McKeigue PM, Lithell HO, Leon DA. Glucose tolerance and resistance to insulin-
University of Edinburgh
stimulated glucose uptake in men aged 70 years in relation to size at birth. Dia-betologia. 1998;41:1133-1138.
Western General Hospital
4. Forster E. An improved general method to generate internal standards for com-
Edinburgh, Scotland
petitive PCR. Biotechniques. 1994;16:18-20.
Paul M. McKeigue, PhD
5. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR. Glucocorticoid ex-
posure in late gestation permanently programs rat hepatic phosphoenolpyruvate
London School of Hygiene and Tropical Medicine
carboxykinase and glucocorticoid receptor expression and causes glucose intoler- London, England
ance in adult offspring. J Clin Invest. 1998;101:2174-2181.
Obituary Listings of US physicians are no longer pub-lished in JAMA. They are now available online on theWeb site of the American Medical Association. Thelisting is now fully searchable and will be updatedmonthly. The listing can be accessed on the AMAHomepage at http://www.ama-assn.org by clicking on“Physicians and Medical Students,” then “News andEvents,” and then “Obituary Listing,” or accessed di-rectly at http://www.ama-assn.org/ama/pub/category/7255.html.
2506 JAMA, May 15, 2002—Vol 287, No. 19 (Reprinted)
2002 American Medical Association. All rights reserved.

Source: http://pla.ce.bo.free.fr/biblio/nocebo_jama_ltte.pdf