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Viewpoint |

Avoiding Nocebo Effects to Optimize Treatment Outcome FREE ONLINE FIRST

Ulrike Bingel, MD, PhD1 ; For the Placebo Competence Team
[+] Author Affiliations
1Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
JAMA. Published online July 07, 2014. doi:10.1001/jama.2014.8342
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Published online

Converging evidence suggests that the occurrence of unwanted adverse events during drug treatment is in part determined by nonpharmacological effects. For instance, the majority of unwanted adverse effects and symptoms reported by patients in clinical trials often are not caused by the medication, because unwanted adverse effects can also occur to a comparable degree in the placebo group of the study.1 Similarly, the switch from brand name to generic drugs with identical compounds is frequently associated with an increase in unwanted adverse effects and therefore could lead to treatment discontinuation. These examples highlight that patients’ expectations regarding adverse effects are important determinants of unwanted adverse effects during drug treatment.

Negative expectations not only determine the occurrence of unwanted adverse effects but can affect the therapeutic efficacy of the drug. A pharmacological study using functional magnetic resonance imaging showed that negative treatment expectancy abolished the analgesic effect of the potent µ-opioid remifentanil at the behavioral and neural level.2 Similarly, a recent study of acute migraine treatment revealed that falsely labeling the 5HT1B/1D agonist rizatriptan as placebo significantly reduced its efficacy.3 Observations from clinical crossover trials and experimental evidence indicate that negative expectations or prior experience transfer over time, and treatment can hamper the effect of subsequent treatment.4

These negative effects on treatment efficacy and tolerability induced or driven by psychological factors are referred to as nocebo effects. Although mechanisms related to nocebo effects are less well understood than those related to placebo effects,5 these effects are not the result of bias but have neurobiological2 and peripheral physiological substrates.6 Nocebo effects can be triggered by psychosocial and contextual factors. The mechanisms best supported by empirical evidence are expectancy (ie, patients’ expectations regarding the effect of a treatment) and learning processes induced by pretreatment experiences such as the prior occurrence of unwanted adverse effects or prior treatment failure.5 Learning processes mediating nocebo effects do not necessarily have to be based on firsthand experience but also can be the result of “social contagion.”6 For instance, reporting of unwanted adverse effects to official centers for adverse reaction monitoring has been shown to increase following public media coverage of adverse treatment responses.7 In addition, patient-clinician communication plays a pivotal role in moderating these effects, as for instance shown in a study on epidural anesthesia for labor pain, in which minimal variations in phrasing the potential occurrence of discomfort modulated pain associated with the procedure.8

Collectively, nocebo effects could substantially reduce treatment efficacy and tolerability and therefore patients’ adherence and compliance, and could play a major role in their withdrawal from necessary treatment. Physicians should be aware of ways by which they unintentionally induce nocebo effects and be familiar with strategies to prevent or minimize nocebo effects.9 Based on the key mechanisms underlying nocebo effects—expectation, learning processes, and the crucial influence of physician-patient communication—the Placebo Competence Team proposes strategies to minimize nocebo effects (Box). These strategies target different levels of the health care system, including medical training, medical practice, legal aspects (ie, informed consent procedures), and the involvement of media.

Box Section Ref ID

Box.
Possible Strategies to Prevent the Development of Unwanted Adverse Effects Related to Medications
Expectation and Learning-Based Interventions
  • Optimize treatment expectation and expectation of adverse effects

  • Balance the presentation of adverse effects and desired effects

  • Teach and train strategies to cope with adverse effects

  • Refer to web-based and other information systems that provide evidence-based information, instead of unproven, anxiety-increasing comments

  • Improve the design, layout, and content of drug leaflets including mechanisms and targeted drug effects, lay language, and patient-oriented presentation of probabilities (graphical instead of numerical)

  • Use “hidden” tapering-in or withdrawal of medication (patients are informed a priori that drug dosage will be modified but are unaware of the timing and pace of the modifications)

  • Use pretreatment with low adverse effect rates

  • Use observational learning, eg, use video clips with patient examples coping well with adverse effects

Patient-Physician Communication
  • Adapt an authentic and empathic communication style

  • Provide adequate information regarding disease, diagnoses, treatments and adverse effects

  • Provide systematic use of feedback to patients

  • Ask proactive check-back questions (ask patients to summarize provided information) to prevent negative biases and misunderstandings

  • Assess and address patients’ anxieties, concerns, and expectations

Physicians, nurses, other health care professionals, and allied health services should be aware of their responsibility to avoid and reduce nocebo effects and the detrimental consequences of these effects, from diagnosis to therapy to prognosis. For instance, information about potential adverse drugs effects should be combined with a detailed explanation of the desired therapeutic effects. The benefit of taking a medication (“this drug will reduce your risk of stroke by 20%”) should always be included in patient information about newly prescribed drugs. Patients should be encouraged to use coping strategies instead of discontinuing treatment when unpleasant but transient and benign reverse effects occur. Moreover, the effects of negative expectation can be reduced through the use of “hidden” applications in which patients are informed a priori that the drug dosage will be modified if necessary but are unaware of the exact timing and pace of the modifications because the drug is provided in capsules or diluted in juice. Examples are the hidden tapering-in of drugs with a known high probability for accompanying adverse effects or the hidden withdrawal of drugs likely to induce withdrawal symptoms.

In addition to these strategies, empathic patient-physician communication is known to help prevent unwanted adverse effects. For instance, medical jargon is likely to cause misunderstandings and trigger fear in patients (eg, “Screening for tumors was negative”). A patient-centered communication style is therefore required when explaining diagnostic procedures, their results, and the rationale and implementation of any intervention. Knowledge of nocebo effects and the importance of communication competence for health outcomes should be reflected in the curricula of future health care professionals.

From a legal standpoint, improved patient information systems such as drug information leaflets (package inserts) should be designed to reduce negative expectations regarding unwanted adverse effects. At present, all potential adverse events must be listed for legal reasons and must be stated using standardized terminology, although empirical evidence for a causal link between drug and unwanted adverse effects is poor. Instead, public-oriented and patient-oriented language and presentation of desired and unwanted effects should be an integral part of any information leaflet. This should include ways to convey abstract information such as the probability of the occurrence of adverse effects, rather than just listing all possible unwanted adverse effects.

The past decades have seen important advances in the development of new diagnostic tools and treatments. However, this progress has also led to increased specialization, shortened consultation times, and lower therapeutic alliance. In addition, the context of unwanted adverse effects has changed, with reports of underreporting in clinical trials and greater public awareness. Incorporating mechanisms-based strategies into the clinical context that help to avoid nocebo effects, including a scientifically grounded communication competence, has the potential to optimize treatment efficacy and adherence.

ARTICLE INFORMATION

Corresponding Author: Ulrike Bingel, MD, PhD, Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany (ulrike.bingel@uk-essen.de). Members of the Placebo Competence Team are listed at the end of this Viewpoint.

Published Online: July 7, 2014. doi:10.1001/jama.2014.8342.

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving a grant payable to her institution from the German Research Foundation; receiving a grant from Pfizer; and receiving payment for lectures from Grünenthal, Teva, Ipsen, and Bionorica.

Funding/Support: This work was supported by the German Research Foundation (FOR-1328).

Role of the Sponsor: The German Research Foundation had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication.

Members of the Placebo Competence Team: Ulrike Bingel, MD, PhD, Paul Enck, PhD, Winfried Rief, PhD, and Manfred Schedlowski, PhD.

REFERENCES

Rief  W, Avorn  J, Barsky  AJ.  Medication-attributed adverse effects in placebo groups: implications for assessment of adverse effects. Arch Intern Med. 2006;166(2):155-160.
PubMed   |  Link to Article
Bingel  U, Wanigasekera  V, Wiech  K,  et al.  The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011;3(70):70ra14.
PubMed   |  Link to Article
Kam-Hansen  S, Jakubowski  M, Kelley  JM,  et al.  Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med. 2014;6(218):ra5.
PubMed   |  Link to Article
Kessner  S, Wiech  K, Forkmann  K, Ploner  M, Bingel  U.  The effect of treatment history on therapeutic outcome: an experimental approach. JAMA Intern Med. 2013;173(15):1468-1469.
PubMed   |  Link to Article
Enck  P, Bingel  U, Schedlowski  M, Rief  W.  The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov. 2013;12(3):191-204.
PubMed   |  Link to Article
Benedetti  F, Durando  J, Vighetti  S.  Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway. Pain. 2014;155(5):921-928.
PubMed   |  Link to Article
Faasse  K, Cundy  T, Petrie  KJ.  Medicine and the Media: thyroxine: anatomy of a health scare. BMJ. 2009;339:b5613.
PubMed   |  Link to Article
Varelmann  D, Pancaro  C, Cappiello  EC, Camann  WR.  Nocebo-induced hyperalgesia during local anesthetic injection. Anesth Analg. 2010;110(3):868-870.
PubMed   |  Link to Article
Colloca  L, Finniss  D.  Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA. 2012;307(6):567-568.
PubMed   |  Link to Article

Figures

Tables

References

Rief  W, Avorn  J, Barsky  AJ.  Medication-attributed adverse effects in placebo groups: implications for assessment of adverse effects. Arch Intern Med. 2006;166(2):155-160.
PubMed   |  Link to Article
Bingel  U, Wanigasekera  V, Wiech  K,  et al.  The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011;3(70):70ra14.
PubMed   |  Link to Article
Kam-Hansen  S, Jakubowski  M, Kelley  JM,  et al.  Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med. 2014;6(218):ra5.
PubMed   |  Link to Article
Kessner  S, Wiech  K, Forkmann  K, Ploner  M, Bingel  U.  The effect of treatment history on therapeutic outcome: an experimental approach. JAMA Intern Med. 2013;173(15):1468-1469.
PubMed   |  Link to Article
Enck  P, Bingel  U, Schedlowski  M, Rief  W.  The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov. 2013;12(3):191-204.
PubMed   |  Link to Article
Benedetti  F, Durando  J, Vighetti  S.  Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway. Pain. 2014;155(5):921-928.
PubMed   |  Link to Article
Faasse  K, Cundy  T, Petrie  KJ.  Medicine and the Media: thyroxine: anatomy of a health scare. BMJ. 2009;339:b5613.
PubMed   |  Link to Article
Varelmann  D, Pancaro  C, Cappiello  EC, Camann  WR.  Nocebo-induced hyperalgesia during local anesthetic injection. Anesth Analg. 2010;110(3):868-870.
PubMed   |  Link to Article
Colloca  L, Finniss  D.  Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA. 2012;307(6):567-568.
PubMed   |  Link to Article

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