Original article
Gender and the nocebo response following conditioning and expectancy

https://doi.org/10.1016/j.jpsychores.2008.09.019Get rights and content

Abstract

Objective

To investigate the role of Pavlovian conditioning and expectancy and of gender on the nocebo effects.

Methods

Conditioning experiment: Forty-eight healthy male and female volunteers were investigated for 3 days using a standard rotation procedure. Subjects in the experimental group received a salient oral stimulus prior to rotation; subjects in the control group received the stimulus 12 h after rotations on Days 1 and 2; on Day 3, all subjects received the stimulus prior to rotation. Expectancy experiment: Another 48 healthy subjects were rotated 5×1 min once only. All subjects received the same oral stimulus immediately prior to rotation; subjects in the experimental group were told that the symptoms might worsen with the stimulus; controls did not receive additional information. In both experiments, symptom rating (SR) and rotation tolerance (RT) were determined.

Results

Conditioning significantly reduced RT (P=.015) and increased SR (P=.024). For both RT and SR, a significant “day×group×gender” effect was found (P=.044; SR: P=.011) indicating that conditioning was more effective in women. Expectancies lowered RT (P=.085) without affecting SR. There was a significant “rotation×gender” interaction on RT (P=.005) indicating that the expectancy was more effective in men.

Conclusion

Women responded stronger to conditioning while men responded to expectancies, but to a lesser degree. It needs to be determined whether this is restricted to nausea-specific conditions or can be generalized across clinical and experimental conditions.

Introduction

The rising placebo response (PR) in clinical trials, e.g., in psychiatry [1], pain therapy [2], and functional bowel disorders [3], has raised concerns not only about future chances to test and approve drugs for various medical indications but also about the underlying mechanisms of the PR both in clinical trials and in everyday medicine.

We [3] and others [4], [5] have postulated that—beyond methodological errors resulting in “regression to the mean”—the mechanisms that underlie the PR are twofold: Pavlovian conditioning on the one hand and expectancy on the other [6], i.e., suggestions by physicians and respective expectations by the patients, that manipulate the ability to perceive symptoms and their changes in a “noisy” environment, e.g., with variable symptom intensity and frequency.

Both mechanisms have been tested and approved to exist in specific experimental and clinical conditions such as in placebo analgesia [5], [7], with motor control in Parkinson's disease [8], depression [1], mania [9], and functional bowel disorders [3], [10]. However, these mechanisms have not been tested for the contribution of gender, despite the fact that Pavlovian conditioning, habituation, and other learning procedures are known to be more effective in women than in men [11], [12], [13]. Gender differences in placebo analgesia have, however, been noted [14]. It is also unknown whether both mechanisms are effective in similar clinical (or experimental) situations, and whether their effect size is comparable. Finally, ongoing discussion [15], [16], [17] has questioned whether the nocebo response follows the same rules as the PR, but experimental data on this issue is scarce.

For clinical trials, e.g., in functional bowel disorders, only a few factors contributing to placebo such as the number of study visits and the severity of the disease have been identified [3], and gender has not been among them. This may be due to the fact that in clinical trials, the amount of conditioning and expectancy elements is usually not known and may be highly variable, as may be the number of males and females included [16].

Therefore, we investigated the relative contribution of gender in two independent experiments—one on conditioning and one on expectancy of a nocebo response—with similar procedures and in identical experimental settings. We hypothesized that both procedures would elicit nocebo responses similar in size and would not be different between men and women.

Section snippets

Subjects

The studies were conducted at two institutions, the Institute of Medical Psychology, University Hospitals Düsseldorf, Germany, and the Department of Psychosomatic Medicine, University Hospitals Tübingen, Germany, and by independent female experimenters (SK, SB) in 2006. The ethics boards of both institutions had approved the experimental protocols prior to the studies being performed. All subjects gave written informed consent before participation.

All subjects were healthy volunteers recruited

Anticipatory nausea

Baseline SR on Day 3 compared to Day 1 was affected by “gender” [F(1,44)=4.45, P=.041] and a significant interaction “day×group×gender” [F(1,44)=4.19, P=.047] was found: symptoms increased from Day 1 to Day 3 in men in the control condition, and in women in the conditioning group, but the change was stronger in women (Fig. 1).

Post-rotation nausea

Across all 3 days, RT decreased significantly [main effect of days: F(2,44)=5.01, P=.011] indicating sensitization. Conditioning significantly reduced RT in comparison to

Discussion

Gender differences in the prevalence of nausea and vomiting have been described for many clinical conditions [20], [21], [22], [23], [24] and have been attributed to differences in symptom awareness and the willingness to acknowledge such symptoms in socially controlled situations [25]. Previous reports from our group [11], [12], [13], [20] have raised doubts on this common belief. We found in learning experiments with healthy male and female subjects that higher susceptibility to motion in

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    This study was supported by a grant from Deutsche Forschungsgemeinschaft (En 50/25-1).

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    Died May 20th, 2008.

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