Placebo Responses in Irritable Bowel Syndrome
found a significant correlation of the PR in terms of symptom improvement and remission with the country in which the study was performed, with higher PR when the study was carried out exclusively in the US. Also, clinical improvement (endoscopic remission) showed an inverse correlation with diary-keeping during the study and the duration of the trial. The number of participants explained a significant amount of the variance for histologic improvement, again emphasizing the possible involvement of regression to the mean. In ulcerative colitis, the correlation between the PR and the response in the drug arm were highly correlated (r=0.56; p<0.01), indicating that 25–30% of the drug response may be attributable to placebo (including spontaneous remission).
The PR in Crohn’s disease (CD) averaged 18% for remission (symptom reduction below clinical cut-off) and 19% for response (symptom reduction by degree), both measures being highly correlated; however, significant inter-study variability (range 0–50%) was noted.17
In ulcerative colitis, the PR was up to 40% in terms of the clinical benefits, more than 30% for endoscopic remission, and around 25% for histologic remission; however, it also depended on the number of study visits, and was significantly lower with three or fewer visits compared with four or more visits during the trial.15 analysis16
Another meta-
Table 1: Treatment Studies in Irritable Bowel Syndrome with Gain Above Placebo (Percentage) and Number Needed to Treat
Drug Source
Peppermint oil Ford, 20084 SSRIs TCA
Ford, 20095 Ford, 20095
Spasmolytics Ford, 20084 Cilansetron Alosetron
Ford, 20096 Ford, 20096
Domperidon Lesbros, 20047 Probiotics Tegaserod Fibers
Cisapride
Renzapride Total
Hoveyda, 20098 Ford, 20096 Ford, 20084 Ford, 20096 Ford, 20096
Studies (n) Total (n) Gain (%)* NNT** 4 5 9
392 230 575
23 3 8 3 7
11 12 4 3
92
1,878 2,229 4,987 176 895
9,242 611 317 726
22,258
*Percentage gain = percentage of responders in the medication arm minus percentage of responders in the placebo arm of the studies, averaged across all studies of the respective intervention group. **Number needed to treat (NNT) in the drug arm to have at least one patient more in the medication arm improved compared with the placebo arm, averaged across all studies of the respective intervention group, and given as range. SSRIs = selective serotonin re-uptake inhibitors; TCA = tricyclic antidepressants.
Predictors
of the PR in terms of remission were the number of study visits, study duration, and severity of disease at entry. As with other conditions (depression, functional bowel disorders),18–21
severity of disease at entry
was inversely correlated to the size of the PR. PR responders showed significantly lower symptom severity scales at study entry, while no such relationship was found for the drug response.
The PRs in terms of relapse and endoscopic recurrence in post- operative CD range around 24 and 50%, respectively. Whereas duration of follow-up has been identified as a predictor of clinical relapse, no single variable was significantly correlated with endoscopic recurrence.
In duodenal ulcer, the PR rate ranged between 0 and 100% (with an average of about 40%) according to Moerman et al.22
The rate
depended on the medication regimen: among 79 studies, healing rates were 6–8% higher with the four-times-a-day versus a twice-a- day regimen.23
due to a high rate of ‘spontaneous indicating significant additional 0.20
A moderate correlation between treatment and placebo response rates (r=0.49; p<0.001) across trials indicated a moderate ‘pure’ drug effect23
healing’ in both groups. Ulcer treatment studies, sorted according to nationality and location, showed a negative correlation between placebo and drug response rates,24
cultural, social, or socioeconomic factors in the efficacy of the placebo treatment.
Placebo Response Rates in Experimental and Clinical Pain
A meta-analysis across 114 placebo-controlled clinical trials (in 40 medical conditions, including pain treatment) that included a ‘no treatment’ control group by Hrobjartsson and Gotzsche25 with another 52 trials26
and an update reported effect sizes for the placebos to be
rather small, e.g. <10% pain reduction on a 10cm visual analog scale (VAS). The authors concluded that spontaneous variation and recovery of the symptoms provide a major contribution to the PR (as well as to
US GASTROENTEROLOGY & HEPATOLOGY REVIEW
In an analysis of studies on placebo analgesia (usually performed in healthy subjects and with experimental pain) in comparison with clinical studies of the PR in drug trials in patients who experience pain,28
Vase et al. found the overall effect size of the experimental 29 0.00 10 100 1,000 Total number of patients
Placebo-response rate measured as percentage; number of patients is log-transformed. All trials were randomized, double-blind, and placebo-controlled. It is evident that with sample sizes >500 the placebo response tends toward 40%.
the drug response) noted in clinical trials. In an attempt to differentiate between spontaneous remission and ‘true’ PR, the authors conducted a further meta-analysis of 37 three-arm trials that included both a placebo group and a ‘no treatment’ control group.27
They showed spontaneous
healing to be high in symptoms such as nausea, depression, phobia, and pain; nearly 50% of the PR was due to spontaneous remission.
10,000
Figure 1: Correlation Between Placebo Response Rates and Number of Patients in the Placebo Arm of 92 Irritable Bowel Syndrome Studies
1.00 0.80 0.60 0.40
38.7 26.7 18.4 16.9 16.3 14.5 10.2 9.9 8.8 4.3 3.6
-3.91
2–3 3–4 5–6 5–6 6–7 6–7
9–10
10–11 11–12 23–24 28–29 -25–26
Placebo response
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