In this repeated-measures pilot study in which active-drug and placebo effects were assessed in patients with asthma, two different types of placebo had no objective bronchodilator effect beyond the improvement that occurred when patients received no intervention of any kind and simply underwent repeated spirometry (no-intervention control). In contrast, the subjective improvement in asthma symptoms with both inhaled placebo and sham acupuncture was significantly greater than the subjective improvement with the no-intervention control and was similar to that with the active drug. Thus, even though there was a large, objective drug effect (mean percent improvement in FEV1, 20%) that was nearly three times the effect of the two placebos and the no-intervention control (mean percent improvement in FEV1, approximately 7% for all three), patients could not reliably detect the difference between this robust effect of the active drug and the effects of inhaled placebo and sham acupuncture (mean subjective improvement reported by all patients, regardless of intervention, ranged between 45 and 50%).
For the objective physiological outcome (change in FEV1), there was a powerful medication effect (drug vs. placebo) but no placebo effect (no difference between placebo and the no-intervention control). For the subjective outcome, the placebo effects were equivalent to the drug effect, and all were greater than the no-intervention effect. The two placebo interventions had a strong effect on the patient-reported outcome but had no effect on the objective outcome; the active drug had a strong effect on the objective outcome but had no incremental benefit with respect to the subjective outcome.
Most randomized, controlled trials and laboratory experiments have not included a no-intervention control. Our inclusion of a no-intervention control — the control for the placebos — allowed us to detect subjective placebo effects. We found that the results of placebo interventions did not differ from those of the no-intervention control when an objective measure of airflow was used (FEV1). However, for the subjective outcome, both placebos had a greater effect than no intervention. This may have been due to the effect of the patient’s expectation on the patient-reported outcome or to reporting bias (e.g., the wish to please the investigator). We consider the latter influence unlikely because the patients receiving no intervention also reported subjective improvement, even though they presumably had no expectation of improvement and their wish to please the investigator would have made a report of no improvement more likely. Our findings might have been influenced by possible weaknesses in the scale used to assess subjective responses (which lacked prior formal validation). However, it is unlikely that the findings were due to the instrument used, since patients receiving no intervention did not show such an effect.
The subjective responses to placebo were equivalent to the subjective responses to the active drug, even though the active drug produced a marked increase in FEV1. Thus, the administration of a placebo did not affect the objective measure (placebo as compared with the natural history of asthma), and the effect of the active medication did not exceed that of the ritual of the treatment itself (albuterol as compared with either placebo). The fact that the patient-reported outcome was independent of the physiological outcome suggests either that patients with asthma poorly perceive changes in FEV1 or that use of subjective assessment may have some limitations in the interpretation of physiological outcomes in asthma and may have upper limits, possibly explaining why asthma symptoms in many patients remain uncontrolled. Furthermore, it can justly be asserted that for self-appraised symptoms, placebos can have a powerful effect.
It is notable that the two placebos had similar effects on both the objective measure and the subjective measure. Since all the patients had prior experience with active inhalers, one might have expected better outcomes with the placebo inhaler than with sham acupuncture, owing to classical conditioning. One possible reason for the apparent equivalence of the two placebo interventions is that the patients may have become conditioned to the setting and personnel at a well-known hospital as much as to the inhaler itself. Another possible explanation is that the remarkably high credibility of sham acupuncture in our study (85%, vs. 66% for the placebo inhaler), which is consistent with the findings in previous studies, might have resulted in a greater expectation of improvement with sham acupuncture.
Our findings complement the results of a recent randomized, controlled trial that examined the effects of optimistic drug presentation (enhanced positive expectations) on outcomes with placebo or active medication (montelukast) in 610 patients with asthma.14
Placebo given with enhanced expectations significantly increased subjective outcomes but had no effect on objective measures, whereas enhanced expectations for medication influenced neither subjective nor objective outcomes. Although another study of asthma reported objective improvement with placebo,8
it lacked a no-intervention comparison, so it is not known whether the reported improvement reflected an actual effect of placebo or simply the natural history of asthma. Our findings strongly contrast with a series of studies in which placebo interventions plus strong suggestion resulted in marked changes in FEV1
in patients with asthma.15,16
In these studies, the patients were deceptively told that they were receiving “powerful” medication, whereas our study was conducted with neutral double-blind instructions. Most of these other studies lacked no-intervention controls, and the two studies that included them showed no placebo effect.17,18
Although placebo effects may differ according to the specific disease,19,20
our study has implications for understanding placebo effects in general. Our findings are consistent with those of a meta-analysis involving multiple conditions, in which the placebos, as compared with no-intervention controls, had no significant effect on objective measures but did have significant effects on subjective outcomes (e.g., pain).4
Also, our data support recent systematic reviews of studies that involved specific conditions, suggesting that placebo effects are primarily detectable in subjective outcomes; when objective changes occur, they tend to be well within the range of the natural history of the condition.21
Furthermore, our findings do not contradict recent laboratory studies showing that placebo treatment elicits quantifiable changes in neurotransmitters and regionally specific brain activity that influence symptoms.1
The bifurcation of placebo effects between objective and subjective outcomes that we observed in this pilot study may represent the distinction that social scientists make between treating disease (objective physiology) and treating illness (subjective perceptions).22,23
Although effective medications target and modulate objective biologic features, the mere ritual of treatment may affect patients’ self-monitoring and subjective experience of their disease.24
Our subjective measure deserves comment. Since there were no preexisting subjective measures for the acute asthma response, we constructed our own metric for global subjective assessment of improvement in dyspnea; as a result, its reliability and validity can be questioned. However, our measure had good face validity. Even though similar measures are common in medicine and have been shown to have good reliability and validity (e.g., the Borg scale, which is used to assess dyspnea), none have been validated for use in assessing either asthma or the acute bronchodilator response.25
In addition, patients used the entire range of the measure, and there were no ceiling or floor effects. The broad range of responses and roughly normal distribution argue against the existence of strong acquiescence (tendency to agree regardless of the content of a question) or central-tendency biases. Our subjective scale did not encompass worsening of symptoms (i.e., the scale measured improvement, from none to complete); thus, it could indicate a perceived lack of improvement but not a perceived worsening. This limitation could potentially create a floor effect and underestimate the degree of subjective deterioration for some patients. However, there was no floor effect observed in the distribution of assessment scores for the active or placebo interventions. In contrast, there was, as expected, a floor effect with the no-intervention control, since patients assigned to this control overwhelmingly reported no improvement. This floor effect serves to strengthen our findings concerning the discrepancy between subjective and objective outcomes. It does so because the only significant difference with respect to the subjective outcome was the lower degree of improvement in the no-intervention condition as compared with the other three conditions. Thus, the floor effect for the no-intervention control would, if anything, have served to diminish the difference between no intervention and the active and placebo interventions and would have decreased our ability to detect such a difference.
This study has several other limitations. First, we studied acute asthmatic responses, so it remains unclear whether our findings would apply to chronic asthma or to other conditions. Even with respect to the treatment of acute asthma, it is important that the findings from our study be replicated to assess their reliability and robustness. In addition, we measured outcomes using a single subjective measure and a single objective measure (FEV1
). Future research should investigate whether our findings can be generalized to other subjective and objective measures of acute asthma. Finally, we did not assess subjective symptoms before each visit’s intervention; therefore, the severity of subjective symptoms before each treatment remains unclear. Assessing subjective measurements before and after interventions could have yielded other differences. Although it is possible that the degree of physiological deficit in these patients was not sufficient for them to have symptoms at rest, it is increasingly recognized that not all patients with asthma who have deficits in lung function fully appreciate the degree to which their asthma limits airflow until they are given bronchodilators that result in improvement in lung function, symptoms, or both.26-28
In this study, there was a significant improvement in lung function with the genuine bronchodilator (about 20%) that coincided with an improvement in symptoms, whereas treatment with placebo had no effect on measurable biologic factors but was indistinguishable from medication with regard to subjective outcomes.
Our research has important implications both for the treatment of asthma and for clinical-trial design in general. Many patients with asthma have symptoms that remain uncontrolled, and the discrepancy between objective pulmonary function and patients’ self-reports noted in this study suggests that subjective improvement in asthma should be interpreted with caution and that objective outcomes should be more heavily relied on for optimal asthma care. Indeed, although improvement in objective measures of lung function would be expected to correlate with subjective measures, our study suggests that in clinical trials, reliance solely on subjective outcomes may be inherently unreliable, since they may be significantly influenced by placebo effects. However, even though objective physiological measures (e.g., FEV1) are important, other outcomes such as emergency room visits and quality-of-life metrics may be more clinically relevant to patients and physicians. Although placebos remain an essential component of clinical trials to validate objective findings, assessment of the course of the disease without treatment, if medically appropriate, is essential in the evaluation of patient-reported outcomes.