The International Continence Society (ICS) 2020 online meeting opened with a presentation by Dr. Alan Wein, previous Chief of Urology at the University of Pennsylvania, now Director of the Penn Urology Residency Training Program. Dr. Wein presented an informative lecture on the effectiveness of the “placebo” in clinical research. He reviewed the results of the proof of concept study of stress urinary incontinence (SUI) in post-menopausal women with an enobosarm (GTX-024), a synthetic androgen receptor analog, presented previously at the 2017 International Continence Society (ICS) and the 2018 American Urological Association (AUA) annual meetings.
This small study showed a 50% reduction in urinary incontinence (UI) episodes which were sustained for seven months after trial completion. However, a subsequent larger double-blind placebo-controlled study showed that placebo was just as effective as two different doses of the enobosarm agent. Dr. Wein noted the placebo effect of several studies on overactive bladder (OAB) symptoms, including incontinence episodes and urgency. Placebo effects have not been not only limited to OAB, but are also seen in other studies including irrtable bowel syndrome (IBS), ulcerative colitis, Chron's disease, depression, and erectile dysfunction. There was a tendency in these studies to see a decrease in the placebo effect by lengthening the run-in period. In addition to decreasing pain, placebo activated endogenous opioids have been shown to affect the respiratory centers (depression) and the cardiovascular system (decreased pain). Surprisingly, there have been reports of the placebo effect on dopamine release in drug studies in Parkinson’s disease, but Dr. Wein noted there is a difference between the placebo response (change in the placebo arm in a clinical trial) and the placebo effect (the mechanism by which a placebo response occurs).
Henry Beecher first noted the placebo effect in a case during World War II. The medic had run out of morphine and had a high-risk and agitated soldier in severe pain. The nurse injected saline and told the patient he was getting a pain injection. The patient calmed immediately, had little pain, and did not go into shock during the procedure. Dr. Beecher then started a “placebo” program at Harvard and published his findings in the Journal of the American Medical Association (JAMA). Dr. Beecher also noted that a placebo could also have adverse effects. Dr. Zubieta et al. found that placebo effects on pain may equal 8 mg of morphine as it can trigger endorphin production in the brain which parallels the decrease in pain perception. These placebo effects can reduce neural activity in brain areas known to produce anxiety and pain which was proportional to decreases in pain ratings.
Dr. Wein noted that experiments of giving an open view of an opioid injection (the patient sees the injection) are more effective in reducing pain than a "hidden from patient view" injection. Dr. Benedetti et al. noted that a placebo can activate the same biochemical pathways as drugs. As to how long a placebo effect will last, Dr. Wein noted it depends on the expectations of the patient and the invasiveness of the treatment. Placebo effects can last beyond the length of a study as shown in research of fetal tissue transplantation versus sham surgery for Parkinson’s disease. Patients who believed they received the tissue were significantly improved whether they had sham or fetal tissue for up to 12 months. The long-term effects of a placebo have been shown in studies on tamsulosin (over a year) and finasteride (over 8 months). But there does not appear to be a relationship of a placebo effect to demographics, age, or personality.
Increased frequency of dosing has a higher placebo response and trials with longer "run-in" periods have lower placebo response during the actual trial. Dr. Wein presented a trial of albuterol which showed the placebo response in subjective improvement in the acute asthmatic response but not in objective measures. Dr. Chen et al. showed that clinicians transmit beliefs to patients and that providers' "expectations about the efficacy of a treatment can substantially affect patient treatment outcomes through social cues". Providers send non-verbal information that communicates their beliefs about whether a treatment may be effective or not, a “socially transmitted placebo effect". There are other factors that may affect placebo response: the more expensive the intervention, the more effective; devices have a greater effect than a pill, and surgery is greater than injection treatment.
Dr. Wein ended the lecture with recommendations to enhance placebo effects including emphasizing the positive effects of an intervention and limiting the emphasis on major side effects by noting how uncommon they are. He notes that it is important to always provide a positive message and allow adequate time to listen to the patient, understanding expectations and concerns. Dr. Wein’s opinion is that we need to investigate the placebo effect in clinical trials of OAB and other lower urinary tract symptoms.
Written by: Diane Newman, DNP, CRNP, FAAN, BCB-PMD, Nurse Practitioner (NP), Co-Director, Penn Center for Continence and Pelvic Health Director, Clinical Trials, Division of Urology, Adjunct Professor of Urology in Surgery, Penn Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
References:
1. Benedetti, Fabrizio, Elisa Frisaldi, and Aziz Shaibani. "Placebo effects: the need for a new perspective and conceptualization." Expert review of clinical pharmacology 11, no. 6 (2018): 543-544.
2. Chen, Pin-Hao A., Jin Hyun Cheong, Eshin Jolly, Hirsh Elhence, Tor D. Wager, and Luke J. Chang. "Socially transmitted placebo effects." Nature Human Behaviour 3, no. 12 (2019): 1295-1305.
3. McRae, Cynthia, Eva Cherin, T. Gayle Yamazaki, Gretchen Diem, Alexander H. Vo, Dan Russell, J. Heiner Ellgring et al. "Effects of perceived treatment on quality of life and medical outcomesin a double-blind placebo surgery trial." Archives of general psychiatry 61, no. 4 (2004): 412-420.
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6. Zubieta, Jon-Kar, Joshua A. Bueller, Lisa R. Jackson, David J. Scott, Yanjun Xu, Robert A. Koeppe, Thomas E. Nichols, and Christian S. Stohler. "Placebo effects mediated by endogenous opioid activity on μ-opioid receptors." Journal of Neuroscience 25, no. 34 (2005): 7754-7762.