Nonspecific Medication Side Effects and the Nocebo Phenomenon

SPECIAL COMMUNICATION

Arthur J. Barsky, MD Patients taking active medications frequently experience adverse, nonspe- Ralph Saintfort, MD cific side effects that are not a direct result of the specific pharmacological Malcolm P. Rogers, MD action of the drug. Although this phenomenon is common, distressing, and Jonathan F. Borus, MD costly, it is rarely studied and poorly understood. The nocebo phenomenon, in which placebos produce adverse side effects, offers some insight into non- LMOST 3 BILLION PRESCRIP- specific side effect reporting. We performed a focused review of the litera- tions are filled each year in ture, which identified several factors that appear to be associated with the outpatient settings in the nocebo phenomenon and/or reporting of nonspecific side effects while tak- United States, an increase of 50%A since 1992.1 Although many side ing active medication: the patient’s expectations of adverse effects at the effects (generally defined as an action outset of treatment; a process of conditioning in which the patient learns of a drug other than the one for which from prior experiences to associate medication-taking with somatic symp- it is being used) result directly from toms; certain psychological characteristics such as anxiety, depression, and these drugs’ pharmacological activity, the tendency to somatize; and situational and contextual factors. Physi- many others cannot be attributed to cians and other health care personnel can attempt to ameliorate nonspecific their specific pharmacological ac- side effects to active medications by identifying in advance those patients tions. These nonspecific side effects distress patients, add to the burden of their most at risk for developing them and by using a collaborative relationship illness, and increase the costs of their with the patient to explain and help the patient to understand and tolerate care. They may lead to nonadherence, these bothersome but nonharmful symptoms. cause physicians to discontinue what JAMA. 2002;287:622-627 www.jama.com is otherwise an appropriate therapy, or prompt attempts to treat these side ef- effects may be positive and beneficial or its beneficial, therapeutic effects,2-4 and fects with additional drugs. negative and adverse. In this article, we in this article it will be used broadly to In this article, we use the nocebo phe- are concerned only with the latter, and refer to all distressing symptoms that nomenon to explore the occurrence of in the interests of brevity will use the accompany placebo administration. adverse, nonspecific side effects in pa- general term “nonspecific side effects” tients taking active medication and sug- to refer only to negative or adverse symp- Methods gest ways in which clinicians can deal toms or physical changes. Similarly, the We conducted a focused review of ar- more effectively with them. Side effects term “side effects” will be used to refer ticles relevant to the nature, inci- occurring in patients taking active medi- to unintended adverse effects. dence, magnitude, and medical man- cation may be divided into 2 types. “Spe- The nocebo phenomenon may help agement of nonspecific medication side cific side effects” are symptoms or physi- us understand (adverse) nonspecific effects. The MEDLINE database was ological changes that result directly from side effects. The nocebo (meaning in searched for English-language articles the specific biological and pharmaco- Latin “I will harm”) phenomenon re- from 1966 through the present, using logical activity of the drug and tend to fers to symptoms and/or physiological the following Medical Subject Head- be dose-dependent and predictable. changes that follow the administra- ings (MeSH) terms: adverse effects, side “Nonspecific side effects” are symp- tion of an inert, chemically inactive sub- effects, symptoms, nocebo, placebo, drug toms or physiological changes that can- stance that the patient believes to be an Author Affiliations: Department of Psychiatry, Brigham not be explained on the basis of the active drug. The term nocebo was origi- and Women’s Hospital and Harvard Medical School, known pharmacology of the drug and nally coined to distinguish the nox- Boston, Mass. Corresponding Author and Reprints: Arthur J. Bar- are idiosyncratic and not dose- ious or distressing effects of a placebo sky, MD, Department of Psychiatry, Brigham and dependent. In theory, nonspecific side (meaning in Latin “I will please”) from Women’s Hospital, 75 Francis St, Boston, MA 02115.

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reaction, and ambulatory care. The tients receiving a placebo device re- tributable to the drug’s specific, phar- search was extended using the bibliog- ported intensification of their preexist- macological activity. By analogy, we raphies of pertinent recent articles and ing pain.14 Second, the symptoms may suggest here that some fraction of the reviews. Articles were screened for rel- be the somatic concomitants of emo- side effects experienced by the pa- evance based on the title, key words, tion (such as anxiety or depression) or tients taking an active drug can be at- and abstracts. Articles were reviewed, of psychosocial stress. Third, patients tributed to the nocebo effect.18 analyzed, and synthesized, but no for- may mistakenly ascribe the symptoms of Approximately one quarter of pa- mal meta-analysis was conducted for 2 mild infirmities or benign, self-limited ail- tients taking placebo report adverse side reasons: first, this article is not in- ments (such as headaches, cramps, and effects.19,20 (In one striking example, hy- tended to be a systematic or compre- extrasystoles) or of normal physiologi- pervagotonia manifested by an idio- hensive summary of the literature, but cal functioning (eg, orthostatic dizzi- ventricular rhythm occurred with pla- rather a focused review. Second, the re- ness) to the medication. To explore the cebo administration in a double-blind search is too variable in methods and similarity between reported side effects study of a calcium channel blocker.21) quality for any standardized compari- and such endemic symptoms, Reiden- Rosenzweig et al22 found that 19% of son. More weight, however, was given berg and Lowenthal15 ascertained the in- healthy volunteers taking placebos in to empirical studies using more rigor- cidence of 25 commonly reported symp- 109 double-blind, placebo-controlled ous sample selection, comparison toms in healthy persons who were not trials spontaneously reported adverse groups, more sophisticated analytic taking any medicines. Thirty-nine per- side effects. In an earlier survey of 67 methods, and standardized assess- cent reported fatigue, 26% difficulty con- placebo-controlled trials, an average of ment tools. centrating, 23% drowsiness, 14% head- 23% of patients taking placebo spon- ache, and 5% dizziness15; only 19% of the taneously reported at least 1 bother- The Incidence and Nature of respondents reported experiencing no some side effect.23 When subjects are Nonspecific Side Effects symptoms in the previous 3 days. In a actively queried about side effects, a In 1995, drug-related adverse effects more recent study, Khosla et al16 found substantially higher incidence (be- and illnesses were estimated to ac- that 73% of 236 healthy volunteers tween 27% and 71%) is found.24-27 count for $76.6 billion in hospital costs who were not taking any medications In placebo-controlled trials for dis- and 17 million emergency depart- reported symptoms in the preceding eases that are largely asymptomatic, the ment visits in the United States.5 Most 3 days. The most common were fa- incidence of nocebo side effects may studies have focused on the incidence tigue, headache, difficulty concentrat- equal or even exceed the incidence of side of serious side effects among hospital- ing, and somnolence. effects reported by patients taking the ac- ized patients and little attention has Thus, when a patient starts taking a tive drug. Thus, in trials of antihyper- been devoted to nonspecific side ef- new medication, there is already a large tensive medications and agents to treat fects in ambulatory settings.6-9 In gen- reservoir of bodily symptoms avail- cerebrovascular insufficiency, side- eral, only a small fraction of such side able for misattribution by the patient effect rates among those taking placebo effects are reported,10,11 due in part to to the medication. This misattribution are comparable to those reported tak- uncertainty as to whether the symp- is more likely to occur in: (1) patients ing an active drug,17,28-30 and headache toms were definitely caused by the who expect to experience side effects; in particular is more common among medication. In one study of drugs com- (2) patients who have been previously those taking placebo.17,28 Many commonly prescribed in primary care prac- conditioned to experience side ef- monly reported nocebo symptoms are tice, 10.9% of reported adverse effects fects; (3) patients who have particular generalized and diffuse such as drowsi- were clearly attributable to the medi- psychological characteristics; and (4) ness, nausea, fatigue, and insomnia.13 In cation, 68.7% were judged to be prob- certain circumstances and conditions. summarizing a large number of studies, ably related, and 20.3% were thought Before discussing each of these 4 risk headache occurred in 7% of those tak- possibly related.12 factors, however, it is necessary to re- ing placebo, drowsiness in 5%, weak- These nonspecific symptoms may arise view the nocebo phenomenon. ness in 4%, dizziness in 1%, and nausea from a variety of sources, since a large in 1%.22 In another study, somnolence reservoir of preexisting, ambiguous so- The Nocebo Phenomenon was found in 25% of those taking pla- matic symptoms are available for attri- The placebo effect is assumed to oc- cebo, fatigue in 17%, gastrointestinal bution to a newly instituted medica- cur in patients taking active drugs and complaints in 16%, difficulty concen- tion. First, the symptoms of the therefore to account for some fraction trating in 13%, and headache in 12%.31 underlying disease for which the pa- of that drug’s total therapeutic effect. The mechanisms underlying the no- tient is being treated may be mistakenly A placebo control group17 is impor- cebo phenomenon remain unclear. ascribed to the medication.13 For ex- tant in drug trials because it allows re- Conditioned learning and expectancy ample, in a randomized controlled trial searchers to determine that fraction of effects (discussed in the following sec- of an analgesic device, 12% of the pa- the overall treatment effect that is at- tion) have been implicated.32-34 A pos-

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sible biological basis is suggested by the ticipating centers specifically listed “gas- obstruction” while they breathe in- recent finding that cholecystokinin me- trointestinal irritation” as a possible side duces more upper airway symptoms diates the hyperalgesia that can result effect, while the consent form at the third than instructing them to attend to the from the administration of a placebo center did not.43 Patients at the former “free passage of air.”41 Community resi- and that proglumide (a cholecystoki- institutions reported a significantly dents who mistakenly believe they have nin antagonist) blocks this nocebo higher incidence of gastrointestinal been exposed to a toxic substance or haz- effect.35 Nocebo symptoms occur sig- symptoms, but did not have a higher in- ardous waste have an increased inci- nificantly more often in women than in cidence of confirmed gastrointestinal dis- dence of symptoms that they ascribe to men.30,36-38 Although cultural and eth- ease than the patients whose consent the supposed exposure.49,50 nic factors are thought to be impor- forms did not mention these side ef- Prior Conditioning. Patients may tant, little empirical evidence exists.39 fects and 6 times as many patients in the manifest side effects to a prescribed In controlled clinical trials, these no- former group withdrew from the study medication not because of its specific cebo effects can be severe enough to because of gastrointestinal distress.43 The pharmacological actions, but rather be- lead to discontinuation and dropout information given a patient about a drug cause they have experienced side ef- from the trial,17 yet three quarters of pa- modifies his/her expectations of it and fects to other drugs in the past. This oc- tients and a like number of health care therefore his/her response to it.33 Thus, curs as a result of classical conditioning professionals (nurses) are not aware of among patients given a muscle relax- in which a neutral, inert, or inactive the nocebo phenomenon.40 One prac- ant, those who were told it was a stimu- stimulus (such as a substance, person, tical implication of this ignorance is that lant reported greater muscle tension than or procedure) acquires the capacity to patients receiving placebo in a clinical those who were told it was a relaxant.33 elicit a physiological change (for ex- trial who experience side effects may Similarly, when an aerosolized, active ample, in blood pressure, immune re- conclude that they are taking an ac- bronchoconstrictor (carbachol) was ad- sponse, or airway resistance) if it has tive drug, which could in turn reduce ministered to asthmatic subjects, it pro- previously been repeatedly paired with the treatment effect.40 The nocebo effect duced more airway resistance and dys- a provocative stimulus.51 In this way, furnishes a justification for including pnea in patients who were told it was a patients can become conditioned to de- placebos in clinical trials since it per- bronchoconstrictor than in those who velop medication side effects. Condi- mits a more accurate appraisal of the were told it was a brochodilator.44 Ap- tioned nausea is seen in as many as 33% side-effect profile of the active medi- proximately one half of asthmatic pa- of chemotherapy patients52-54 who be- cation. Without such a placebo com- tients inhaling nebulized saline who come profoundly nauseated when en- parison, the active medication may be were informed that it was an allergen de- countering a previously neutral stimu- associated with side effects that are not veloped dyspnea, increased airway re- lus that has now become associated in fact specifically attributable to it, but sistance, and decreased vital capac- with the chemotherapy, such as meet- rather are the nonspecific conse- ity,45,46 and when patients with food ing the infusion nurse outside the hos- quences of taking any medication and allergies are injected with saline that is pital or entering a room painted the due to interindividual differences. described as an allergen, one quarter de- same color as the infusion room. velop allergic symptoms.47 In another Conditioned responses have been ob- Factors Associated With study, pain patients’ initial expecta- served in patients with asthma and other Nonspecific Side Effects tions of discomfort associated with the allergies. Asthmatic attacks can be pre- Expectation and Suggestion.Patients placement of a sham analgesic device cipitated by presenting patients with a who expect distressing side effects be- were associated with increased pain re- sealed glass jar filled with dust or with fore taking a medication are more likely ports.14 The ethical issues (eg, decep- a plastic rose to smell.46,55 Residents of to develop them. Such negative expec- tion of subjects) inherent in such stud- communities close to hazardous waste tations make the individual more likely ies are generally not addressed in these sites display a similar response. Thus, the to notice and attend to new or unwel- reports, perhaps indicating that our cur- occurrence of malodorous air and un- come sensations; interpret preexist- rent heightened sensitivity to such con- pleasant-tasting water (widely associ- ing, ambiguous, and vague sensations siderations is relatively recent. ated with contamination, pollution, or unfavorably and attribute them to the Expectations also induce symptoms poisoning) in a community was fol- medication; and overlook positive in healthy nonpatients. More than two lowed by an increased incidence of dis- changes and evidence of symptom re- thirds of healthy volunteers experi- tressing somatic symptoms; however, air mission.24,41,42 enced a headache after being told that sampling and water quality evalua- Several studies illustrate the role of a mild electric current that induces head- tions disclosed no evidence of toxic con- negative expectations and suggestion. In ache would be passed through their taminants.56 a multicenter, placebo-controlled trial of heads, although no electricity was ad- Psychological Characteristics. Sev- aspirin treatment for unstable angina, the ministered.48 Instructing volunteers to eral psychological characteristics, in- informed consent form at 2 of the par- pay attention to any evidence of “nasal cluding anxiety, depression, and soma-

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tization, have been associated with side sation has also been associated with in- Some attributes of pills (eg, size, effects to active drugs and with nocebo creased symptom reporting following color, shape, and even the name) may symptoms.57,58 Clinicians have noted that placebo administration.65,66 influence the likelihood or nature of the side effects reported by highly anx- Situational and Contextual Influ- nonspecific side effects. Red, orange, ious patients are often the somatic con- ences. Nonspecific side effect report- and yellow tablets are associated with comitants of anxiety itself (eg, tachycar- ing is influenced by the context and en- stimulant effects, and blue and green dia, dyspnea, or sweating).59 Although vironment in which the medication is suggest sedative effects.74 Thus, volun- empirical evidence is lacking, de- given, and by the physical and sym- teers taking blue placebos report more pressed patients also seem particularly bolic characteristics of the medication drowsiness then those taking pink pla- prone to medication side effects. Bodily itself. Although clinical experience sup- cebos.75 Color is also associated with distress is often an integral feature of de- ports this widespread conviction that specific sites of action: red is associ- pression: depressed patients are somati- situational characteristics (eg, the set- ated with cardiac activity, and tan and cally preoccupied, expect to suffer and ting and environment in which medi- beige with dermatological activity.76 experience discomfort, and don’t feel cation is prescribed) and interper- they deserve to get better. Symptoms ex- sonal factors (such as the nature of the Clinical Implications perienced as medication side effects also patient-physician relationship) influ- Maintain a High Index of Suspicion for serve as the rationale for nonadherence ence the incidence and nature of side Side Effects That Are More Properly to the medication regimen, and approxi- effects,67,68 there is little rigorous, em- Ascribed to the Patient Than to the mately one third of depressed patients in pirical evidence about this. Drug. When a patient reports trouble- primary care practice stop taking anti- The characteristics of the medica- some side effects, the clinician should depressants within the first month of tion itself, both physical and sym- not automatically assume they result treatment.60,61 Finally, higher levels of bolic, can also influence side effects. The from the pharmacological action of the generalized psychological distress pre- symbolic properties that the patient medication and therefore necessitate a dispose people to reporting nonspecific attributes to the medication reflect the dosage adjustment, discontinuation, or side effects. Thus, neuroticism (a gen- information, opinions, and beliefs the addition of another medication to eralized and enduring tendency to ex- he/she has about it. These may be pow- treat them. A heightened index of sus- perience a wide range of psychological erfully shaped by the mass media and picion is called for when the patient’s symptoms and emotional distress) ap- other sources of information such as the symptoms are vague, ambiguous, or pears to be associated with the nocebo Internet and the direct advertising and prevalent in daily life; when the pa- effect.29 marketing of pharmaceuticals to the tient has a history of negative side ef- A tendency toward somatization, general public. Erroneous informa- fects to many different classes of drug; symptom amplification, and a height- tion and misunderstandings may fos- and when the patient is exceptionally ened awareness of bodily sensation have ter anxiety, suspicions, and a sense of anxious about, or even seems to ex- also been associated with nonspecific side vulnerability, all of which can amplify pect, difficulties with the medication. effects. Measures of somatization are as- benign bodily sensations and cause In such cases, a change in the regimen sociated with an increased likelihood of them to be misattributed to the medi- may not be necessary and may even be developing pain at the site of a placebo cation. Because of their historical repu- counterproductive. injection in patients with chronic tem- tation, some medications may be more Identify at the Outset Those Pa- poromandibular joint pain,62 and a mea- likely to have adverse effects ascribed tients Most at Risk for Nonspecific sure of hypochondriasis predicted side- to them. For example, penicillin al- Side Effects. Patients who somatize or effect reporting in healthy, nondepressed lergy is widely recognized by the pub- who are anxious or depressed are at volunteers taking an antidepressant.29 In lic, and up to 10% of hospitalized pa- greater risk of nonspecific side effects. a study of patients switching from a stan- tients report being allergic to it.69 Ask patients about prior “bad experi- dard anxiolytic to an extended-release However, on careful investigation, 97% ences” with drugs, whether they con- form, baseline measures of somatiza- of adults70 and 94% of children71 la- sider themselves “especially sensitive” tion significantly predicted the subse- beled as “penicillin allergic” were found to drugs, and inquire about a history quent incidence of adverse side ef- to tolerate oral penicillin. It was sug- of medically unexplained complaints. fects.63 In patients with rheumatoid gested that these patients had misin- Pointing out that the anticipation or fear arthritis, self-report measures of soma- terpreted coincidental symptoms as al- of an adverse reaction can become a self- tization and of the tendency to amplify lergic in origin, or labeled as allergic fulfilling prophecy (by causing the mi- benign bodily sensations were signifi- some symptoms that were actually due sattribution of unrelated, preexisting cant predictors of medication side ef- to the underlying illness (eg, sore symptoms to the newly instituted drug) fects over the ensuing 3 months, even af- throat).72 Thus, the fear of a penicillin may in itself help to obviate some non- ter controlling for arthritis severity.64 A reaction may deprive many patients of specific side effects. It may also be help- heightened awareness of autonomic sen- an effective treatment.73 ful to discuss the nocebo phenom-

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enon explicitly with such patients. It tants of emotion or of normal physiol- of all bothersome symptoms, but rather may help to explain how somatic symp- ogy, to the new medication. The goal to help patients tolerate them. toms caused by preexisting medical ill- here is not to eliminate the side effects, Physicians also help patients toler- nesses or by anxiety and depression, but rather to help the patient tolerate ate side effects by remaining available and those that are simply endemic to them; patients who understand the ba- to discuss them and to provide reas- daily life, can be misattributed to a sis of their somatic distress are less fright- surance and encouragement. Keeping newly instituted medication. ened by it and find it more bearable. It the patient’s expectations of pharma- Use a 2-Step, Collaborative Strat- can be useful to clarify that although the cotherapy modest and realistic is also egy for Prescribing. For patients at risk patient’s symptoms are distressing, they wise; overselling the virtues of a medi- of nonspecific side effects, pharmaco- are not medically dangerous and do not cation and downplaying its side ef- therapy may be undertaken in collabo- indicate bodily harm. A study of pa- fects may lead to eventual dismay when ration with the patient in 2 discrete tients with functional gastrointestinal dis- they do occur. Conversely, physician phases with distinctly different goals. orders treated with atropine provides em- frustration, irritation, or dissatisfac- The goal of the first phase is simply to pirical evidence that the way in which tion with the patient may exacerbate the help the patient tolerate a very low dose side effects are framed affects overall outpatient’s discomfort and ultimately, his/ of medication; therapy is initiated at come.67 The physical well-being ratings her side effects. doses that may be subtherapeutic, with of these patients differed significantly de- Include Other Health Care Person- the objective of allowing the patient to pending on whether the specific medi- nel in the Process. Outpatients often get used to the idea of taking a medication side effect of dry mouth was pre- discuss their side effects with nurses, cation. Because the symptoms of the un- sented favorably (as a sign the medicine pharmacists, physician assistants, and derlying medical condition are likely to was taking effect and should be ig- other health care personnel. It is im- persist during this first phase of phar- nored) or unfavorably (as a possible toxic portant that these professionals under- macotherapy, the patient may con- effect that might require discontinua- stand the issues and know about the clude prematurely that the medication of the medication).67 possible sources of nonspecific side ef- tion is ineffective, so it is important to If Side Effects Occur, Find Out if the fects, so that they can provide the in- explain that such a gradual titration may Patient Is Dissatisfied With His/Her formation, explanation, reassurance, mean that the symptoms of his/her ill- Care. If bothersome side effects oc- and encouragement needed. ness will persist a while longer. In the cur, it can be useful to ask patients second phase of therapy, the dose is about any dissatisfactions they may Conclusions gradually increased into the therapeu- have with their medical care in gen- Nonspecific medication side effects are tic range, acknowledging whatever side eral. Patients may harbor misgivings, distressing and frightening to pa- effects develop, and coupling this with uneasiness, or suspicions about their tients. They result in wasted medica- support and encouragement. Patients treatment, but may feel uneasy about tion and nonadherence, physician vis- should be reassured that although the voicing these concerns openly. Report- its that are not medically necessary, and nonspecific side effects may be both- ing troublesome side effects may be a unnecessarily complicated regimens ersome, they are not medically danger- less confrontational way of expressing when additional drugs are added to treat ous. Patients may be encouraged to re- such disaffection. Nonspecific side ef- these side effects. Because this phenom- search a drug (eg, on the Internet), as fects may then be a nonverbal state- enon is common, distressing, and long as the results of this search are then ment of patients’ misgivings about treat- costly, it deserves greater clinical scru- discussed with their physician. Tim- ment; such side effects provide an tiny and more empirical investigation. ing can be crucial: some patients sim- acceptable excuse for not taking the Future research should focus on iden- ply need more time to initiate treat- medication, without having to openly tifying the personal characteristics and ment. It is usually unwise to pressure refuse it or directly confront the clini- situational influences that make non- apprehensive and ambivalent patients cian with reservations about their care. specific side effects more likely to oc- into premature acquiescence, as this in- The clinician should ask patients if they cur, and on developing effective clini- sistence can exacerbate side effects. suspect that the wrong diagnosis has cal strategies to ameliorate them.

If Nonspecific Side Effects Occur, been made or the wrong medication Author Contributions: Study concept and design: Provide an Explanation and Help the Pa- prescribed. Would they prefer some Barsky, Rogers. tient Reattribute Them. If nonspecific other treatment? Do they believe they Acquisition of data: Barsky, Saintfort, Rogers. Analysis and interpretation of data: Barsky, Saint- side effects occur, it is helpful to dis- are receiving too many pills? Though fort, Borus. cuss the process of symptom misattri- it may not be possible to accommo- Drafting of the manuscript: Barsky, Saintfort, Rogers. bution described earlier and to explore date the patient’s concerns, elucidat- Critical revision of the manuscript for important whether the patient may have relabeled ing and discussing them may help to intellectual content: Barsky, Saintfort, Borus. Administrative, technical, or material support: or misattributed the symptoms of his/ reestablish a collaborative alliance. Barsky, Borus. her disease, or the somatic concomi- Again, the goal is not the elimination Study supervision: Barsky.

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