In a pilot study designed to tease out placebo effects from genuine clinical responses, asthma patients rated albuterol and two placebo interventions as effective, yet only the albuterol objectively improved forced expiratory volume in 1 second, according to a report in the July 14 issue of the New England Journal of Medicine.
The 46 study subjects also rated both placebo interventions as superior to a no-intervention control situation, even though the objective forced expiratory volume in 1 second (FEV1) response was nearly identical in all three, said Dr. Michael E. Wechsler of the division of pulmonary and critical care medicine, Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his associates.
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Patients in this study could not reliably detect the difference between the effects of inhaled albuterol and placebo interventions.
"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%)," they wrote.
These findings suggest that asthma patients poorly perceive changes in FEV1 and that subjective assessments in clinical studies of asthma are severely limited. "Furthermore, it can justly be asserted that for self-appraised symptoms, placebos can have a powerful effect," Dr. Wechsler and his colleagues said.
Their results may also have important implications for placebo effects in general, not just in asthma patients. "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," the investigators said.
They chose asthma patients as ideal subjects for this pilot study of placebo effects because repeated objective lung-function assessments can be performed over a short period of time. "We compared acute changes in lung function that occurred after repeated administration of four interventions: a masked bronchodilator (inhaled albuterol), two different types of placebo (an inert inhaler and a validated sham acupuncture needle), and a [waiting] period of no intervention."
A total of 46 adults with stable, mild to moderate asthma who had experience using inhalers were enrolled. They were assigned to each of the four interventions in random order on four separate occasions, 3-7 days apart. On each occasion, they underwent spirometry at baseline and at 20-minute intervals for 2 hours following the intervention. The study subjects documented their subjective treatment responses using a 10-point visual analog scale.
The mean percent improvement in FEV1 was 20.1% for inhaled albuterol, compared with 7.5% for inhaled placebo, 7.3% for sham acupuncture, and 7.1% for the no-intervention control situation of sitting in a waiting room. This constitutes a "significant" and "large" difference between active and nonactive interventions.
Moreover, using a standard definition of treatment response (12% or greater improvement in FEV1), patients using the albuterol inhaler responded 77% of the time, while those using the placebo inhaler responded 24% of the time, those using sham acupuncture responded 20% of the time, and those using no intervention responded 18% of the time, Dr. Wechsler and his associates said (N. Engl. J. Med. 2011;365:119-26).
However, the subjects’ assessments did not reflect these results. They reported a 50% improvement in asthma symptoms with inhaled albuterol, a 45% improvement with inhaled placebo, and a 46% improvement with sham acupuncture, compared with a significantly lower 21% improvement with no intervention.
Patients were asked whether they thought they had received active or placebo interventions. Most believed all the interventions except sitting in a waiting room were active. A total of 73% believed the albuterol was active, 66% believed the placebo inhaler was active, and "a remarkable" 85% believed the sham acupuncture was active.
The study findings complement those of a recent trial in which placebo given with "enhanced expectations" – such as deceptive remarks that subjects were receiving a powerful medication – had no effect on objective outcomes but did increase subjective response.
Dr. Wechsler and his colleagues said their results suggest that "subjective improvement in asthma should be interpreted with caution and that objective outcomes should be more heavily relied on for optimal asthma care."
But this interpretation can be questioned. Dr. Wechsler and his colleagues concluded that asthma patients’ reports were "unreliable" because "they reported improvement when there was none – that is, the subjective experiences were simply wrong because they ignored objective facts as measured by FEV1," Daniel E. Moerman, Ph.D., wrote in an editorial accompanying Dr. Wechsler’s report (N. Engl. J. Med. 2011;365:171-2).