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Placebo/Nocebo Effect in Rosacea

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Understanding the psychology of treating rosacea can better help you find a way to control your rosacea, since emotional pain can be a huge factor in your life. To complete the picture, you should have a basic understanding of the placebo/nocebo effect in treatments for your rosacea. Your mind plays a significant factor in whether a treatment for rosacea works for you or not. The placebo/nocebo effect is real and you need to understand why treatments for rosacea usually have a double blind, placebo controlled, peer reviewed clinical study (the current term is Randomized controlled trial). What is the placebo effect? Below are some helpful articles you can read about to help you better treat your rosacea using the placebo effect for your benefit and avoiding the nocebo effect which is negative. We all have a certain amount of bias towards a rosacea treatment which is sometimes based upon real or erroneous facts, which may explain what we have dubbed the X-Factor in rosacea. This bias has a huge bearing on the placebo/nocebo effect. 

An interesting article in The New York Times Magazine states, "Enough people reported good results that patients were continually lined up at Mesmer’s door waiting for the next session."  Dr. Mesmer is where the word mesmerize comes from. The article explains how 'double blind' placebo controlled clinical studies originated and why drug companies have to differentiate between a drug's actual pharmaceutical effect and the placebo effect. I particularly like this paragraph in the article: 

"What if, Hall wonders, a treatment fails to work not because the drug and the individual are biochemically incompatible, but rather because in some people the drug interferes with the placebo response, which if properly used might reduce disease? Or conversely, what if the placebo response is, in people with a different variant, working against drug treatments, which would mean that a change in the psychosocial context could make the drug more effective? Everyone may respond to the clinical setting, but there is no reason to think that the response is always positive. According to Hall’s new way of thinking, the placebo effect is not just some constant to be subtracted from the drug effect but an intrinsic part of a complex interaction among genes, drugs and mind. And if she’s right, then one of the cornerstones of modern medicine — the placebo-controlled clinical trial — is deeply flawed."

What if the Placebo Effect Isn’t a Trick?The New York Times Magazine

"Evidence for the relevance of placebo and nocebo effects in dermatology is also increasing...A large proportion of the success or failure of dermatological treatment can be explained by factors other than the treatment mechanisms themselves. Placebo and nocebo effects, in particular, strongly contribute to treatment outcomes, with explained variances comparable to, for example, effects of analgesics or antidepressants....the placebo responses and positive expectations of patients will only endure if they are based on trust in a long‐term authentic relationship. Highly optimistic promises followed by limited effects will probably result in nocebo instead of placebo effects." [1]

"A nocebo effect is said to occur when negative expectations of the patient regarding a treatment cause the treatment to have a more negative effect than it otherwise would have." Wikipedia

"By definition, a nocebo effect is the induction of a symptom perceived as negative by sham treatment and/or by the suggestion of negative expectations. A nocebo response is a negative symptom induced by the patient's own negative expectations and/or by negative suggestions from clinical staff in the absence of any treatment. The underlying mechanisms include learning by Pavlovian conditioning and reaction to expectations induced by verbal information or suggestion. Nocebo responses may come about through unintentional negative suggestion on the part of physicians and nurses. Information about possible complications and negative expectations on the patient's part increases the likelihood of adverse effects. Adverse events under treatment with medications sometimes come about by a nocebo effect." This same article concluded, "Communication training in medical school, residency training, and continuing medical education would be desirable so that physicians can better exploit the power of words to patients' benefit, rather than their detriment." [2]

"Patient expectations, including those generated by the informed consent process, can have a large influence on the side effects that patients feel after starting a new medical treatment....Medical professionals' own negative beliefs about a treatment, especially generic drugs, may further enhance patients' expectations of adverse effects. The news media may also influence expectations, particularly when media attention is directed towards a health or medication scare." [3]

Twenty-nine internationally recognized placebo researchers participated in the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017 and published a paper in 2018 that states, "There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects." [4]

"Placebo/nocebo effects are difficult to disentangle from the natural course of illness or the actual effects of a new drug in a clinical trial. There are known strategies to enhance clinical results by manipulating expectations and conditioning." [5]

In one study, "106 participants who had all received placebo injection, N = 20 (18.9%) wrongly believed they had received endotoxin and were thus considered as nocebo responders. Nocebo responders reported significantly more bodily sickness symptoms, suggesting that the perception of bodily symptoms affected perceived treatment allocation." [6]

"The aim of this review is to evaluate the placebo effect in the treatment of anxiety and depression. Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin or norepinephrine in the brain. However, analyses of the published and the unpublished clinical trial data are consistent in showing that most (if not all) of the benefits of antidepressants in the treatment of depression and anxiety are due to the placebo response, and the difference in improvement between drug and placebo is not clinically meaningful and may be due to breaking blind by both patients and clinicians. Although this conclusion has been the subject of intense controversy, the current article indicates that the data from all of the published meta-analyses report the same results. This is also true of recent meta-analysis of all of the antidepressant data submitted to the Food and Drug Administration (FDA) in the process of seeking drug approval. Also, contrary to previously published results, the new FDA analysis reveals that the placebo response has not increased over time. Other treatments (e.g., psychotherapy and physical exercise) produce the same benefits as antidepressants and do so without the side effects and health risks of the active drugs. Psychotherapy and placebo treatments also show a lower relapse rate than that reported for antidepressant medication." [7]

"The exact biological mechanisms of this process are not known, but cholecystokinergic and dopaminergic systems, changes in the HPA axis, and the endogenous secretion of opioids are thought to be involved." [8]

"In addition to these mechanisms, several other influential elements are at work during the placebo effect. These include the patient-physician relationship, patient’s psychological state and personality, the severity of the medical condition, and environmental circumstances. The patient's genetics may also influence the degree of placebo effect. Researchers are studying how genes can influence the placebo effect in various pathways, including the dopamine, opioid, serotonin, and endocannabinoid systems. Evidence also indicates that the therapeutic benefits of the placebo effect may not impact the pathophysiology of the underlying disease being studied, but rather address the subjective self-appraised symptoms of the disease. Elucidating the underlying mechanisms that mediate the placebo effect may prove beneficial to clinical practice and drug development." [9]

"In randomized clinical trials, patients in the placebo group invariably improve more than individuals outside of the trial who are treated with standard therapies. The nocebo effect, less well known, consists of undesirable responses to therapy resulting from negative patient expectation. Thus, if a physician emphasizes possible adverse events when discussing an impending therapeutic intervention, it is more likely that the patient will experience them." [10]

"Here is a possibly apocryphal anecdote that I was told many years ago when I was working in Massachusetts. A patient with hypertension complained to his or her physician that all previous attempts to control high blood pressure had failed because of “side effects” caused by the various drugs that had been tried. The physician decided to try prescribing a very-low daily dose of hydrochlorothiazide (HCTZ) as the initial therapeutic strategy. At the next office visit, the patient informed the doctor that he or she had stopped taking HCTZ because of severe pain located on one “side” of his or her body. The patient said, “I definitely developed the ‘side effects’ that you said might happen.” This amusing story is an example of the nocebo effect at work!" [10]

End Notes 

[1] Exp Dermatol. 2017 Jan; 26(1): 18–21.
Using the placebo effect: how expectations and learned immune function can optimize dermatological treatments
Andrea W.M. Evers

[2] Dtsch Arztebl Int. 2012 Jun;109(26):459-65. doi: 10.3238/arztebl.2012.0459. Epub 2012 Jun 29.
Nocebo phenomena in medicine: their relevance in everyday clinical practice.
Häuser W, Hansen E, Enck P.

[3] Postgrad Med J. 2013 Sep;89(1055):540-6. doi: 10.1136/postgradmedj-2012-131730. Epub 2013 Jul 10.
The nocebo effect: patient expectations and medication side effects.
Faasse K1, Petrie KJ.

[4] Psychother Psychosom. 2018;87(4):204-210. doi: 10.1159/000490354. Epub 2018 Jun 12.
Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus.
Evers AWM, Colloca L, Blease C, Annoni M, Atlas LY, Benedetti F, Bingel U, Büchel C, Carvalho C, Colagiuri B, Crum AJ, Enck P, Gaab J, Geers AL, Howick J, Jensen KB, Kirsch I, Meissner K, Napadow V, Peerdeman KJ, Raz A, Rief W, Vase L, Wager TD, Wampold BE, Weimer K, Wiech K, Kaptchuk TJ, Klinger R, Kelley JM.

[5] Clin Ther. 2017 Mar;39(3):477-486. doi: 10.1016/j.clinthera.2017.01.031. Epub 2017 Feb 23.
The Placebo and Nocebo Phenomena: Their Clinical Management and Impact on Treatment Outcomes.
Chavarria V, Vian J, Pereira C, Data-Franco J, Fernandes BS, Berk M, Dodd S.

[6] J Child Adolesc Psychopharmacol. 2019 Aug 1. doi: 10.1089/cap.2019.0022. [Epub ahead of print]
The Impact of Placebo Response Rates on Clinical Trial Outcome: A Systematic Review and Meta-Analysis of Antidepressants in Children and Adolescents with Major Depressive Disorder.
Li Y, Huang J, He Y1, Yang J, Lv Y, Liu H, Liang L, Li H, Zheng Q, Li L.

[7] Front Psychiatry. 2019 Jun 13;10:407. doi: 10.3389/fpsyt.2019.00407. eCollection 2019.
Placebo Effect in the Treatment of Depression and Anxiety.
Kirsch I.

[8] Cancer Metastasis Rev. 2019 Jun;38(1-2):315-326. doi: 10.1007/s10555-019-09800-w.
It is not just the drugs that matter: the nocebo effect.
Wojtukiewicz MZ, Politynska B, Skalij P, Tokajuk P, Wojtukiewicz AM, Honn KV.

[9] StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Mar 23.
Placebo Effect.
Munnangi S, Angus LD.

[10] The American Journal of Medicine
Placebo and Nocebo Effects, Medication Bias, and Hearsay
Joseph S. Alpert, MD

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