An Honest Response—Placebos and IBS

Abstract & Commentary

By Russell H. Greenfield, MD, Editor

Synopsis: Findings of this ground-breaking randomized controlled trial suggest that patients with irritable bowel syndrome who receive treatment with placebo tablets, and who are fully aware that they are taking a placebo, have significantly greater relief of symptoms compared with patients who receive no treatment at all. Accessing the placebo effect may not require deception at all.

Source: Kaptchuk TJ, et al: Placebos without deception: A randomized controlled trial in irritable bowel syndrome. PLoS ONE 2010;5:e15591.

The authors of this randomized, controlled, single center study sought to assess the feasibility of recruiting people with irritable bowel syndrome (IBS) to participate in a trial of open-label placebo, and to evaluate whether an open-label placebo pill combined with a persuasive rationale would be more effective than no-treatment in relieving IBS symptoms over the course of 3 weeks' time.

Participants were recruited from advertisements for "a novel mind-body management study of IBS" in newspapers and fliers, and from health care provider referrals. Subjects had to be older than age 18 years, meet Rome III criteria for IBS, and have a score ≥ 150 on the IBS Symptom Severity Scale (IBS-SSS). They were permitted to continue any IBS medications they were taking provided they had been on stable doses for at least 30 days prior to enrollment, and were asked not to make significant medication or lifestyle changes during the trial period.

Participants were randomized into two groups: 1) open-label placebo pill twice daily, or 2) no-treatment. Prior to randomization, patients from both groups met with either a physician (male) or nurse practitioner (female), based solely on practitioner availability, and were asked what they had heard of the "placebo effect." The provider then explained in clear terms that a placebo pill is an inactive substance like a sugar pill containing no medication. This was followed by the reading of a script, lasting approximately 15 minutes, that described the following "four discussion points:" 1) the placebo effect is powerful; 2) the body can automatically respond to taking placebo pills like Pavlov's dogs who salivated when they heard a bell; 3) a positive attitude helps but is not necessary; and 4) taking the pills faithfully is critical. Additionally, participants were told that "placebo pills...have been shown in rigorous clinical testing to produce significant mind-body self-healing processes."

Subjects were told that one-half of them would be receiving an open-label placebo while the other half would receive no treatment, but that each group was critical to the trial. They were also told that each of them would receive management recommendations for IBS symptoms at the end of the trial. The supportive patient-provider relationship and contact time were similar for both groups.

It was at this point, during the last moments of the interview, that subjects were told of their allocation status; those randomized to the open-label placebo group were given a typical prescription medicine bottle that contained blue and maroon gelatin capsule placebo pills, with the label clearly marked "placebo pills—take 2 pills daily." Patients in the no-treatment arm were reminded again of their important role in the trial.

Assessment questionnaires were completed during study visits with the assistance of a blinded assessor at baseline, midpoint (day 11), and completion (day 21). All visits took place in the context of a warm, supportive patient–practitioner relationship. Subjects receiving placebos were given a short reminder about the "four discussion points" after a brief examination during the midpoint visit, while those in the no-treatment arm were encouraged and thanked for their important contributions to the research.

The primary outcome of interest was the result of the IBS Global Improvement Scale (IBS-GIS). Other measures included the IBS-SSS, the IBS-Adequate Relief (IBS-AR), the IBS Quality of Life (IBS-QoL), side effects, and pill counts. At trial's end, subjects were given a short qualitative open-ended check-out questionnaire and asked for written responses, with unique questions posed to each of the two groups (results to be reported elsewhere). Intention-to-treat analysis was employed.

A total of 92 potential subjects were screened and 80 (70% female) were ultimately randomized into the two groups (n = 43 in the no-treatment arm). Participants in the open-label placebo group had significantly better scores on the main outcome measure, the IBS-GIS, at both the midpoint and endpoint measures (5.2 ± 1.0 vs. 4.0 ± 1.1, P < 0.001 and 5.0 ± 1.5 vs. 3.9 ± 1.3, P = 0.002, respectively). Statistically significant differences favoring placebo were identified at both time points for reduction in symptom severity (IBS-SSS) and adequate relief (IBS-AR), and a trend toward significance at the endpoint on improvement in quality of life (IBS-QoL) was noted. No significant differences on any outcome measure were found based on which practitioner (male physician or female nurse practitioner) met with the participants. Based on the responses to qualitative questions, it appeared that subjects understood they were taking a placebo and were not overly disappointed if assigned to the no-treatment group.

The authors conclude that placebos administered without deception in the context of a supportive patient–practitioner relationship and plausible rationale may be an effective treatment for IBS.

Commentary

This study is flat out awesome. It is the first randomized controlled trial to compare an open-label placebo to a no-treatment control, and the results suggest strongly that placebo effects reflecting symptomatic improvements can be accessed without deception. To review, subjects who received the open-label placebo had almost twice the improvement in IBS symptoms experienced by the no-treatment group.

Most practitioners share the belief that beneficial responses to placebo treatment require concealment or deception, and thus raise an ethical dilemma. And yet, as the authors point out, a not insignificant proportion of physicians report having prescribed medications they believe to have no specific effect on a patient's condition. Based on the current study's results, however, perhaps placebos can be offered to patients with promise of benefit, if used in the same context and with positive framing, for any of a variety of disorders whose primarily clinical manifestations are subjective.

The authors note that the diagnosis of IBS, a chronic functional gastrointestinal disorder characterized by abdominal pain and discomfort associated with altered bowel habits, is one of the top 10 reasons for seeking primary care, and that few effective therapies have been identified. They also reference previous research that showed placebo responses in IBS are substantial and clinically significant.

There are methodological challenges to be acknowledged—the means of attracting participation may have biased the sample toward people more open to mind-body therapies; the sample size is relatively small and the study's duration quite short; in light of these latter facts the significant amount of missing data is concerning. Still, the findings are stunning. It seems that practitioners might ethically be able to use the placebo effect to utmost advantage in helping patients with select maladies while still treating them with respect and honesty, all the while continuing to merit their full trust. It seems an "open-label placebo" is no longer an oxymoron.