Are Those IBS Drug Side Effects Real? Study Raises Doubts

For patients with irritable bowel syndrome (IBS), extra-intestinal symptoms often reported as adverse events in drug trials appeared before any treatment and improved over time regardless of sham, placebo, or usual care.

Among 173 IBS patients, the average severity burden of such symptoms significantly dropped from 14.1 at baseline to 9.8 at 6-week study completion on a 75-point scale, reported Sarah Ballou, PhD, of Beth Israel Deaconess Medical Center in Boston, and colleagues, writing in Clinical Gastroenterology and Hepatology.

This change in extra-intestinal symptoms was significant at P<0.001 across all groups:

• 43% with peppermint oil (Cohen's d=0.94, a large effect size)
• 31% with placebo (Cohen's d=0.48)
• 25% with treatment as usual (Cohen's d=0.50, a medium effect size)

Average number of extra-intestinal symptoms -- most commonly nasal congestion, fatigue, irritability, excessive sleepiness, and inability to concentrate -- reported per patient dropped from five at baseline to three by study completion.

"We found that many of the extra-intestinal symptoms that are often reported as adverse events in IBS clinical trials were present, and often more severe, at baseline," the researchers concluded. "Our findings lend support to previous arguments that nonspecific symptoms ought to be assessed systematically at baseline and throughout a clinical trial to improve accuracy in assessing whether any adverse events are attributable to a drug under investigation."

Open-ended questions are often provided during clinical trials to assess adverse events, but this assessment method is not validated and is prone to reporting bias with a potential to underestimate adverse events, Ballou's group noted.

"Seven of the 15 extra-intestinal symptoms measured in this study could have been identified as side effects using a common standard for reporting adverse events in drug trials (that the symptom should occur in at least 2% of the drug group, and at a higher incidence as compared to the placebo group)," the group wrote. "However, 6 out of these 7 symptoms were equally or more prevalent at baseline compared to the final assessment at 6 weeks, and therefore they cannot be side effects to the drug treatment."

For clinical practice, the researchers suggested "systematically assessing symptoms before and after prescribing a medication in order to promote a data-driven dialogue with patients about possible side effects to medications."

Their trial included 173 patients in the double-blind treatment arms of a 6-week randomized clinical trial that compared open-label versus double-blind treatment in IBS. Participants were randomized to receive 180 mg of enteric-coated peppermint oil (n=30), placebo (n=71), or treatment as usual (n=72) from June 2016 to December 2019. Included patients had moderate to severe IBS, as defined by ROME IV criteria and IBS symptom severity score.

While peppermint oil is often used as an IBS treatment, there were no benefits compared with placebo or usual care in the trial, as previously reported. Main results suggested blinding wasn't necessary for placebos in IBS.

Participants (mean age 42, 73% women, 82% white) had to avoid changing their diet, medications, and exercise during the study. An extra-intestinal symptom questionnaire was provided to patients at baseline and the end of the study, in addition to two other validated questionnaires. IBS was characterized as IBS-diarrhea for 33-45%, IBS-mixed for 30-44%, and IBS-constipation for 20-28%.

For individual extra-intestinal symptoms, 41 of 45 patients (91%) experienced a reduction in symptoms, while only 9% had an increase in symptoms.

At baseline, IBS symptom severity was weakly, but significantly associated with extra-intestinal symptom burden.

"To the degree that patients experienced an improvement in their IBS symptoms, they were also likely to experience an improvement in their extra-intestinal symptoms," the group noted.

Patients with higher levels of anxiety and depression also showed more extra-intestinal symptoms at baseline.

There were no significant differences in symptom burden between groups at baseline or at study completion after controlling for baseline levels.

The authors acknowledged several limitations to the data. Researchers collected data from a trial that focused on the placebo effect and was not designed to assess adverse events. Participants were also allowed to continue their IBS medications throughout the study, while on a stable dose for 30 days before enrolling. Medications were not documented at baseline.

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