Drug-Related Information Generates Placebo and Nocebo Responses That Modify the Drug Response

Flaten, Magne Arve; Simonsen, Terje; Olsen, Harald

doi:10.1097/00006842-199903000-00018

Cited by 167 publications

(112 citation statements)

References 15 publications

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“…20 Similarly, healthy subjects who believed that they were given a stimulant reported experiencing increased muscle tension, when in actuality they were receiving a muscle relaxant. 21 Moreover, when participants receive verbal suggestions indicating that pain will increase, the effects associated with this anticipation are strong enough to reverse conditioned placebo analgesia following two days of exposure to nonopioid analgesic, ketorolac. 22 Interestingly, oral administration of an inert substance (talc) along with verbal suggestions of hyperalgesia induced the hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis, as assessed by levels of adrenocorticotropic hormone and plasma concentrations of cortisol.…”

Section: Nocebo Effects Can Shape Drug Actionsmentioning

confidence: 99%

The influence of the nocebo effect in clinical trials

Colloca¹

2012

OAJCT

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Neurobiological and clinical studies have shown that learning mechanisms and expectations of benefits powerfully affect the brain, mind, and body, with the potential of relieving many symptoms during the course of daily clinical practice. Playing the role of antagonist is the "nocebo effect," which results from negative expectations derived from one's beliefs, previous experiences, and his or her clinical encounters that produce negative effects. Research on the nocebo effect indicates that information disclosure and the manner in which information is delivered can contribute to these adverse effects. In this article, we review neurobiological and medical studies relating to the nocebo effect, as these findings are important for the methodology of clinical trials.

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Section: Nocebo Effects Can Shape Drug Actionsmentioning

confidence: 99%

The influence of the nocebo effect in clinical trials

Colloca¹

2012

OAJCT

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“…In cancer patients, for example, pretreatment expectations predicted postchemotherapy nausea independent of prior experience (Roscoe et al, 2000). In an experimental paradigm, manipulation of drug effect information altered side effects in healthy subjects treated with a muscle relaxant (carisoprodol) or placebo (Flaten et al, 1999). In relation to personality measures, higher scores on the neuroticism-stability scale of the Eysenck Personality Questionnaire-Revised (Eysenck and Eysenck, 1991) and the Somatasensory Amplification Scale (Barsky et al, 1988) were linked to greater side effect reporting among healthy subjects treated with an antidepressant (moclobemide) or placebo (Davis et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Neurophysiologic Correlates of Side Effects in Normal Subjects Randomized to Venlafaxine or Placebo

Hunter

Leuchter

Morgan

et al. 2004

Neuropsychopharmacol

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Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n ¼ 15) or venlafaxine IR (n ¼ 17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r ¼ À0.67, po0.003), at 2 weeks (r ¼ À0.77, po0.002), and at 4 weeks (r ¼ À0.77, po0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-inFprior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.

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“…If headache, nausea, insomnia, rash, and so on coincide with the controlled trial, subjects might presume that the investigational drug was the culprit. A heightened propensity to report discomfort during a trial and attribute it to study treatment represents a negative placebo, or a b"nocebo effect" [20,21]. A consequence of this effect, whose frequency and susceptibility factors remain unclear, is that some subjects might decline a trial of post-study treatment that could provide relief.…”

Section: Concerns Relating To Possible Exposure To Unnecessary Treatmmentioning

confidence: 99%

Can keeping clinical trial participants blind to their study treatment adversely affect subsequent care?

Blader¹

2005

Contemporary Clinical Trials

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Subjects in controlled clinical trials obtain experience with study-provided treatment that could inform their further therapy by awareness of the efficacy or inefficacy of the study treatment they received. However, patients in blinded trials typically do not learn right after their participation what treatment they actually received during the study, even though it is possible to do so while maintaining the necessary blinding of investigators. Keeping investigators and subjects blind to treatment assignment throughout a trial is a key element of clinical research methodology, but the value of keeping participants and their medical providers blinded after participation is less certain and may pose risks that include delay in the receipt of efficacious care, exacerbation of symptoms, or prolonged exposure to superfluous or toxic treatment. The significance of these risks is likely to vary with the specific disease and the time course of its response to available therapies. Currently, it seems appropriate for investigators a) to evaluate the risks of keeping subjects blind after participation, b) to justify doing so in relation to serious, identifiable risks to the study's validity and apprise prospective subjects clearly that information about their response to specific treatment during the trial will not be available to guide their post-study care, and c) to consider methods for debriefing subjects before their resumption of open treatment that preserve the integrity of investigator blinding. In the long-run, research on the impact that keeping subjects uninformed about study treatment has on post-study patient outcomes and on study integrity can foster the development of procedures that optimally balance both.

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Drug-Related Information Generates Placebo and Nocebo Responses That Modify the Drug Response

Cited by 167 publications

References 15 publications

The influence of the nocebo effect in clinical trials

The influence of the nocebo effect in clinical trials

Neurophysiologic Correlates of Side Effects in Normal Subjects Randomized to Venlafaxine or Placebo

Can keeping clinical trial participants blind to their study treatment adversely affect subsequent care?

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