When Are Medication Side Effects Due to the Nocebo Phenomenon? To the Editor: In their discussion of the nocebo phenomenon, Dr Barsky and colleagues1 do not adequately address the issue of causality. Like the distinction between "adverse events" (which occur while receiving a drug, irrespective of causality) and "adverse drug reactions" (which have a plausible causal relationship to the drug), any discussion of the nocebo phenomenon should distinguish between adverse events occurring while receiving placebo vs those directly attributable to it. In the studies that Barsky et al cite as offering quantitative support for their position, it is not clear that this distinction has been made, since most clinical trials elicit adverse events by asking questions such as "Have you felt differently in any way since your last visit?" Because it is even more difficult to determine causality for placebos than for active drugs, it will be challenging to obtain accurate information on the magnitude of this important problem. Robert H. Palmer, MD Forest Laboratories, Inc New York, NY 1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622-627. MEDLINE To the Editor: I would like to add 3 clarifications to the article by Dr Barsky and colleagues on nonspecific medication side effects and the nocebo phenomenon.1 First, following the model suggested by Hahn,2 a distinction must be made between the nocebo phenomenon and placebo side effects. According to Hahn, the nocebo hypothesis proposes that expectations of sickness and the affective states associated with such expectations cause such symptoms in patients who expect them. Placebo side effects, on the other hand, occur when expectations of healing produce sickness; that is, when a positive expectation has a negative outcome. Likewise, nocebos may also have side effects; that is, when negative expectations produce positive outcomes or outcomes other than those expected. This distinction is not just a matter of semantics. I suspect that much of what is labeled as the "nocebo phenomenon" represents, in fact, placebo side effects. In patients who somaticize and in those who are diffusely pessimistic, distinguishing between the 2 concepts admittedly may be difficult. The key is that expectations play a causal role in health and healing as well as in sickness.3 Second, the assertion that in clinical trials placebo side effects " . . . could reduce the treatment effect"1 needs more elucidation. Not all placebos are alike. Whereas the most common form of placebo is inactive, other placebos are active, that is, they produce detectable side effects without any therapeutic effects. For example, in the double-blind evaluation of tricyclic antidepressants, atropine can be used in the control group to mimic side effects, thus decreasing the likelihood that either investigators or subjects would infer the correct treatment assignment. Indeed, there are indications that the difference in effectiveness between active drug and placebo is markedly less when an active drug is compared with an active placebo.4 Thus, recent reviews have emphasized the importance of an active placebo control group in drug efficacy trials, due to their superior capacity to maintain blinding.4 Finally, direct evaluation of drug effects, expectancy effects, and their interactions can best be obtained by the balanced placebo design, which yields a 2 2 matrix comprising 4 conditions in which subjects are (1) told they will get a drug and receive the drug, (2) told they will get a drug but receive placebo, (3) told they will not get a drug but receive the drug in disguised form, and (4) told they will not get a drug and receive no drug.5 I recommend that this design be used more often in clinical trials of efficacy evaluation. Opher Caspi, MD, MA Program in Integrative Medicine University of Arizona Tucson 1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622-627. MEDLINE 2. Hahn RA. The nocebo phenomenon: concept, evidence, and implications for public health. Prev Med. 1997;26:607-611. MEDLINE 3. Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H. The role of expectancies in the placebo effect and their use in the delivery of health care: a systematic review. Health Technol Assess. 1999;3:1-96. MEDLINE 4. Salamone JD. A critique of recent studies on placebo effects of antidepressants: importance of research on active placebos. Psychopharmacology. 2000;152:1-6. MEDLINE 5. Kirsch I, Weixel LJ. Double-blind versus deceptive administration of a placebo. Behav Neurosci. 1988;102:319-323. MEDLINE To the Editor: Dr Barsky and colleagues1 discuss mechanisms by which patients who receive placebos may report adverse effects (the "nocebo phenomenon"). While they identify several important factors, such as misattribution of temporally coincident symptoms and perhaps conditioning, they do not consider that placebo ingredients may produce symptoms. There are no regulations dictating what constitutes a placebo; placebo constituents are seldom reported, precluding accountability and input regarding effects of these constituents, and there is no foundation for the assumption that any placebo constituent is truly physiologically inert.2-4 Even substances that are not absorbed can have effects. Sugar pills may affect blood insulin levels with their cascade of physiological effects, and a lactose "placebo" reportedly led to increased dropout rates in the control group in a study of patients with the human immunodeficiency virus, who have high rates of lactose (and sucrose) intolerance5; similarly, lactose placebos were a possible source of markedly increased gastrointestinal side effects in the placebo group in a study of patients with cancer.6 Subjects may react to excipients, stabilizers, dyes, or other elements, and I have cared for one patient whose painful unilateral neuropathy symptoms were ultimately tracedin repeated n-of-1 blinded comparisonto magnesium stearate, a common lubricant in pill formulation. Apparent positive, negative, or neutral effects of an active drug could be spurious consequences of a negative, positive, or same direction results of a placebo, and there are cases in which such effects appear to have occurred.2 Inconsistent findings across studies could result, in some instances, from differences in the agent to which the active drug is compared. But even if placebo constituents have no impact on the primary outcome being studied, the assumption that they can have no effect on adverse symptoms is unsupportable. Thus, physiological effects of the placebo ingredientsin addition to factors like misattribution or perhaps suggestibilitymay influence nocebo effects. Because the manufacture of placebos and designation of their composition are often determined by the companies that manufacture the drug under study, and because the composition is typically unreported, there is potential for conflict of interest in selection of ingredients. For many reasons, then, the full disclosure of both placebo and active drug preparations should be reported. Beatrice Golomb, MD, PhD Department of Medicine University of California, San Diego, School of Medicine La Jolla 1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622-627. MEDLINE 2. Golomb B. Paradox of placebo effect. Nature. 1995;375:530. MEDLINE 3. Golomb BA. Are placebos bearing false witness? Chem Industry. 1995;21:900. 4. Golomb BA. Using placebos. Nature. 1996;379:765. MEDLINE 5. Corazza GR, Ginaldi L, Furia N, Marani-Toro G, Di Giammartino D, Quaglino D. The impact of HIV infection on lactose absorptive capacity. J Infect. 1997;35:31-35. MEDLINE 6. Loprinzi CL, Ellison NM, Schaid DJ, et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst. 1990;82:1127-1132. MEDLINE To the Editor: Dr Barsky and colleagues1 observe that patients who somatize or who are anxious or depressed have better recollection of side effects to antidepressant therapy. While I agree with this observation, there is little support for their suggestion of a collaborative strategy to treat anxious, depressed, or somatizing patients. Depressed patients with elevated anxiety and somatic symptoms receiving usual care for depression have been found to adhere well to antidepressant therapy, and their anxiety and somatization improve with treatment of depression.2, 3 In their list of psychological characteristics associated with side effects, I believe that Barsky et al missed 2 characteristicshealth concerns and conversionthat have been shown to also predict the important clinical outcome of nonadherence in depressed primary care patients.3 Depressed patients with elevated levels of health concerns and conversion appear to interpret side effects as worsening overall health status and are less likely to adhere to antidepressant therapy. The collaborative strategy and reattribution process outlined by Barsky et al may be more appropriately applied to this subgroup of depressed patients. Researchers investigating nonadherence, side effects, and the nocebo effect may want to incorporate psychometric instruments measuring health concerns and conversion along with the more common measures for somatization, anxiety, and depression. Robert Keeley, MD Department of Family Medicine University of Colorado Health Sciences Center Denver 1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287:622-627. MEDLINE 2. Kroenke K, West SL, Swindle R, et al. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. JAMA. 2001;286:2947-2955. MEDLINE 3. Keeley R, Smith M, Miller J. Somatoform symptoms and treatment nonadherence in depressed family medicine outpatients. Arch Fam Med. 2000;9:46-54. MEDLINE In Reply: These letters underscore how complex and complicated a topic the nocebo phenomenon is and how important precise terminology becomes. We agree with Dr Palmer that "adverse events" are distinct from "side effects" and not all adverse events are attributable to the placebo or to the drug. In clinical practice, however, this distinction may be all but impossible to make. This is why we defined "side effects" as any unintended adverse symptom that the patient attributed to the drug. Several of these letters refer to the role of expectancy in the occurrence of side effects, and Dr Caspi accurately points out that the term "nocebo" most properly refers to symptoms that occur when the suggestions, instructions, and/or expectations accompanying the placebo are negative, as exemplified by hexing and voodoo curses. This has been distinguished from "placebo side effects," which occur when the explicit intent and expectations accompanying the placebo are positive and beneficial. In clinical practice, obviously, physicians do not prescribe medication with harmful intent and therefore it is only the patient's negative expectations that are relevant. These letters also point out the complexities inherent in the placebo notion itself. Thus, Caspi notes that several types of placebo may be used in controlled trials. Although most placebos are devoid of all pharmacological activity, a more sophisticated variant is a placebo that produces symptoms resembling the side effect profile of the active drug it is being compared with. Dr Golomb points out that even placebos assumed to be chemically inert may actually have physiological actions that produce symptoms. We agree with her suggestion that the composition of the placebo used in each study should be reported explicitly. Finally, as Dr Keeley notes, side effect reporting is related to the problem of nonadherence. We agree that the combination of depression and elevated health concerns may be particularly likely to result in nonadherence to the therapeutic regimen. Arthur J. Barsky, MD Malcolm P. Rogers, MD Jonathan F. Borus, MD Brigham and Women's Hospital and Harvard Medical School Boston, Mass Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.