Can Nocebo Effects be Managed in Clinical Practice?
By Sarah Ballou, PhD and Anthony Lembo, MD
The Latin word “placebo” translates to “I shall please” in English, which reflects the positive quality of placebo effects. When a patient responds to placebo, it means that their symptoms have improved after taking an inactive medication, or an active medication with little physiologic evidence to support its use for the targeted symptom (e.g using an aspirin to treat nausea). Placebo responses happen in both research trials and in clinical treatment and tend to happen more frequently in conditions associated with chronic, waxing and waning symptoms, such as disorders of gut brain interaction (DGBI), such as irritable bowel syndrome (IBS) or other chronic painful conditions.
In addition to the positive responses observed with placebos, it was also noted that placebos sometimes cause detrimental or adverse effects. The word “nocebo” comes from the Latin word “nocere” meaning “to harm” and describes this lesser-known phenomenon of unwanted or unpleasant reactions to placebos and/or the experience of side effects that are unrelated to an active treatment. While placebo responses are often attributed to a range of factors including conditioning, expectation, and certain genetic and neurobiological factors, nocebo responses are most often attributed to expectation of possible side effects to a treatment.1,2
The impact of expectation and worry on the experience of nocebo effects is best illustrated by observations in clinical trials. Not only is it common for participants in the placebo arms of drug trials to report adverse events, but these participants will also often report side effects that match the quality and severity of those anticipated for the study drug.3, 4, 5 For example, in a meta-analysis of adverse events in placebo arms of migraine studies, including three classes of anti-migraine drugs, it was noted that the adverse events in the placebo drugs matched the adverse events expected to each specific treatment (i.e. anorexia and memory difficulties were reported only in the trials of anticonvulsants, which are known to cause these side effects, but not to NSAIDs or triptans, which are not associated with these side effects).4 Similarly, a meta-analysis evaluating side effects to two different classes of antidepressants, SSRIs vs. TCAs, which are both also commonly used to treat DGBI, found that TCAs produced higher rates of side effects compared to SSRIs in both the treatment and the placebo groups.3 In other words, participants receiving placebo in a TCA trial reported more side effects compared to participants receiving placebo in an SSRI trial. The authors concluded that this must be due, at least in part, to patient expectation of side effects after being informed in detail about possible adverse reactions to the study drug during the consent process.
Two recent studies, both in IBS, have evaluated the natural course of commonly reported adverse events before and during clinical trials. Both studies showed that most reported symptoms in the drug and placebo arms were actually present prior to beginning the study and that, in most cases, they did not become more severe from baseline to end of study.6,7 Interestingly, one of the studies included treatment with a TCA which, as noted above, is thought to be associated with relatively high rates of side effects, and demonstrated that many of the commonly anticipated side effects may in fact exist prior to starting the drug and be falsely attributed to the medication(i.e. nocebo).6 The other study included a clinical trial of peppermint oil, which did not have many anticipated side effects, but clearly showed that non-IBS symptoms reported by patients in both arms of the trial were more severe at before starting the study compared to at the end of the study.7 Results of both studies support the suggestion that the inclusion of systematic assessment of possible side effects before, during, and after a clinical trial would likely produce more accurate estimates of drug-specific adverse events and may reduce nocebo effects reported in clinical trials.3, 8, 9, 10
The clinical impact of nocebo may be even more salient than their effects on clinical trials. Nocebo effects can impair progress in clinical treatment by leading to discontinuation of therapy or poor tolerance of potentially helpful medications. The likelihood of nocebo effects may be increased after patients read drug information inserts on their own 11 and/or after discussing potential side effects with their physician.12, 13 This leads to the question of whether there is anything that can be done to prevent or weaken nocebo effects in order to potentially improve tolerance of medications. Previous research in healthy individuals has demonstrated that the way in which information is provided to patients can impact clinical outcomes. For example, in a trial evaluating side effects of the influenza vaccine, patients were randomized to either be informed of the percentage of patients who did not experience side effects or the percentage of patients who report side effects after the vaccine. The group that received positively framed information (e.g. those who were told that most people tolerate the vaccine well without side effects) reported fewer side effects 3 days after the vaccine when compared with the group told about the percentage who did not tolerate the injection.14 To our knowledge, the effects of information framing on medication tolerance has only been tested in a clinical population once before. In that pilot study, a small sample of patients with DGBI whose physicians had decided to prescribe TCA were randomized to receive either 1) standard of care including discussion of benefits and risks of TCA as well as appropriate clinical encouragement; or 2) standard of care plus an additional description of nocebo effects and their role in medication tolerance. After two weeks, the group receiving education about nocebo effects attributed fewer symptoms to TCAs than the standard group and reported being significantly less bothered by those symptoms.15
Nocebo effects have important implications in research and in clinical care. Studies have shown that expectation of side effects is a significant reason for the development of adverse events with treatments. Importantly, recent studies have shown that altering expectations may reduce nocebo effects, which in turn may improve compliance with treatments and improve patient outcomes.
- Kennedy WP. The nocebo reaction. Med World. 1961 Sep;95:203–205. PMID: 13752532
- Varelmann D, Pancaro C, Cappiello EC, Camann WR. Nocebo-induced hyperalgesia during local anesthetic injection. Anesth Analg. 2010 Mar 1;110(3):868–870. PMID: 20042440
- Rief W, Nestoriuc Y, von Lilienfeld-Toal A, Dogan I, Schreiber F, Hofmann SG, Barsky AJ, Avorn J. Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis. Drug Saf. 2009;32(11):1041–1056. PMID: 19810776
- Amanzio M, Corazzini LL, Vase L, Benedetti F. A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain. 2009 Dec;146(3):261–269. PMID: 19781854
- Häuser W, Bartram C, Bartram-Wunn E, Tölle T. Adverse events attributable to nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy: systematic review. Clin J Pain. 2012 Jun;28(5):437–451. PMID: 22336767
- Thiwan S, Drossman DA, Morris CB, Dalton C, Toner BB, Diamant NE, Hu JB, Whitehead WE, Leserman J, Bangdiwala SI. Not All Side Effects Associated With Tricyclic Antidepressant Therapy Are True Side Effects. Clinical Gastroenterology and Hepatology. 2009 Apr;7(4):446–451.
- Ballou S, Hassan R, Nee J, Iturrino J, Rangan V, Cheng V, Conboy L, Kirsch I, Lembo A, Kaptchuk TJ, Kelley J. Are they side effects? Extra-intestinal symptoms reported during clinical trials of IBS may be more severe at baseline. Clin Gastroenterol Hepatol. 2022 Mar 23;S1542-3565(22)00293–2. PMID: 35339669
- Rief W, Glombiewski JA, Barsky AJ. Generic Assessment of Side Effects [Internet]. 2009. Available from: www.GASE-scale.com
- Rief W, Barsky AJ, Glombiewski JA, Nestoriuc Y, Glaesmer H, Braehler E. Assessing general side effects in clinical trials: reference data from the general population. Pharmacoepidemiol Drug Saf. 2011 Apr;20(4):405–415. PMID: 21442687
- Rief W, Avorn J, Barsky AJ. Medication-Attributed Adverse Effects in Placebo Groups: Implications for Assessment of Adverse Effects. Arch Intern Med. American Medical Association; 2006 Jan 23;166(2):155–160.
- Tan K, Petrie KJ, Faasse K, Bolland MJ, Grey A. Unhelpful information about adverse drug reactions. BMJ. 2014 Aug 12;349:g5019. PMID: 25115975
- Bingel U, Placebo Competence Team. Avoiding nocebo effects to optimize treatment outcome. JAMA. 2014 Aug 20;312(7):693–694. PMID: 25003609
- Häuser W, Hansen E, Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical practice. Dtsch Arztebl Int. 2012 Jun;109(26):459–465. PMCID: PMC3401955
- O’Connor AM, Pennie RA, Dales RE. Framing effects on expectations, decisions, and side effects experienced: the case of influenza immunization. J Clin Epidemiol. 1996 Nov;49(11):1271–1276. PMID: 8892495
- Ballou S, Iturrino J, Rangan V, Cheng V, Kelley JM, Lembo A, Kaptchuk TJ, Nee J. Improving Medication Tolerance: A Pilot Study in Disorders of Gut-brain Interaction Treated With Tricyclic Antidepressants. J Clin Gastroenterol. 2022 Jun 1;56(5):452–456. PMID: 34091518
Anthony Lembo, MD is a Professor of Medicine at Harvard Medical School. He also serves as the Director of the GI Motility Laboratory at the Beth Israel Deaconess Medical Center (BIDMC) Division of Gastroenterology in Boston, MA.