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“One of the most successful physicians I have ever known, has assured me, that he used more bread pills, drops of colored water, and powders of hickory ashes, than of all other medicines put together. It was certainly a pious fraud.”

—Thomas Jefferson (1807)

The power of placebos in medicine has been described for centuries. In the 18th century placebos in medicine were identified as a substance without therapeutic value. In the 19th century, placebos became more of a manner of pleasing the patient rather than treating them.1 By definition, a placebo is a substance without medical effects that benefits the health status because of the patient’s belief that the substance is effective.2 However, some evidence suggests that placebo effects persist even when patients are told that they are receiving an inactive pill, suggesting that placebo effects may be more complex than originally thought.3 Conversely, a nocebo is defined as a substance without medical effects but which worsens the health status of the person taking it by the negative beliefs and expectations of the patient.4 As an example, information disclosure about potential side effects of a treatment may in itself contribute to producing adverse effects.4 Views on the placebo effect vary in different cultures. In Western medicine, a treatment must outperform a placebo to be considered efficacious. However, in some traditional medicine there is less concern over placebo effects, and medicines are deemed efficacious by observational data.5

Research suggests that not all placebos are created equal. Acupuncture placebo, injection placebo, surgery placebo, and topical placebo have all demonstrated greater power than an oral placebo in treating osteoarthritis.6–8 It has been suggested that medical rituals and patient-clinician engagement can augment the placebo effect, with more elaborate placebos having a greater effect on a patient.5 While placebo effects have been most well described in the field of psychiatry, particularly in the treatment of depression, placebo effects can be found in every field of medicine.1 In this review, we discuss mechanisms of placebo and nocebo effects, how they may impact the skin, offer solutions as to how clinicians can use this phenomenon to best serve their patients, and provide future directions for further investigation into these effects.

Potential Mechanisms

There are several proposed mechanisms of the placebo effect, with the expectation model, reflex/Pavlovian conditioning, and the opioid model being the most well-known theories.9 The expectation model postulates that thoughts and beliefs can influence neurochemical reactions in the body, subsequently leading to hormonal and immunological responses. In this model, a placebo effect leads to a true therapeutic response.9–11

Reflex/Pavlov conditioning describes the placebo effect as a learned response to past medical intervention. If patients previously felt better after visiting the doctor’s office and receiving medication, they may begin to associate medical intervention with a reduction in symptoms. In this theory, all medical treatments unintentionally involve a placebo effect, as patients tend to expect improvement of their symptoms when starting a therapy—unless they have reason to doubt the treatment, in which case, a nocebo effect may instead be at play. Conditioning depends heavily on individual and environmental factors. Attributes, such as patient optimism or worry, may contribute to the strength of placebo or nocebo effect,12 respectively. Both the expectation model and reflex conditioning may coexist and complement one another to create the placebo effect.9–11

The opioid model suggests that endorphins are released in response to the placebo stimulus and may serve as the psychological mechanism of expectation and conditioning previously described. This is supported by the fact that placebo analgesia can be reversed with naloxone, an opioid antagonist.13 While placebo responses may require multiple conditioning trials, nocebo responses can occur with as little as one trial.14 Nocebo effects are thought to be modulated by the hormone cholecystokinin (CCK) due to its ability to transform anxiety into pain. Additionally, negative expectations may induce the hypothalamic-pituitary-adrenal axis, increasing adrenocorticotropic hormone (ACTH) and cortisol. Nocebo hyperalgesia can be antagonized with diazepam, suggesting that anxiety underlies the effect.15

Placebo and Nocebo Effects in Dermatology

There is substantial evidence for placebo and nocebo effects in dermatologic conditions and symptoms. Data suggest that placebo and nocebo effects may have similar pathways and roles in the skin as in other conditions, with well-characterized effects, such as pain and depression. Dermatologic conditions are associated with increased anxiety, depression, and other psychological impacts stemming from disease visibility, chronicity, and unpredictability that increase patient vulnerability to nocebo responses. Patients on dermatologic medications that have a wide range of side effects, such as isotretinoin, are also influenced by information they receive from the Internet or others, increasing their susceptibility.16 Perceived side effects can lead to patient discontinuation of treatment or study drop out,17,18 thus the nocebo effect can have significant impact on patient and research outcomes. Additionally, placebo and nocebo effects have been evoked for dermatologically relevant symptoms, such as itch and allergic manifestations, in those with and without dermatologic conditions.

Itch. Itch and conditioned immune function are major areas of applicability of the placebo and nocebo effects in dermatology. As many people without skin conditions and perhaps most patients with a skin condition experience itch at some point in their life, this has significant implications.19 The sensation of itching is unique among physical sensations for being strongly inducible, such as from viewing others scratching, verbal suggestions (such as a lecture about itch),20 or conditioning to increase scratching response. This phenomenon is deemed “contagious itch.”21,22 Such social induction is higher among those with skin conditions such as atopic dermatitis (AD).23

Both placebo and nocebo effects on itch have been illustrated in dermatology. For example, placebo effects can explain at least 30 percent of itch reduction in randomized controlled trials,24 while negative suggestions of pain or itch from application of a stimulus, such as histamine, resulted in greater reports of both itch and pain.25,26 The combination of automatic and conscious processes, such as conditioning and verbal suggestions, has been found to most effectively induce itch placebo and nocebo effects.12,27,28

Itch in AD. Itch sensitization in patients with chronic itch, such as in AD, may potentially be explained by these effects, with suggested neurobiological mechanisms. Nocebo-induced itch was associated with activation of similar brain pathways observed with true itch-inducing allergen, including the dorsolateral prefrontal cortex, striatum, and intraparietal sulcus. These regions are critical for executive function, attention, and motivational processing. Additionally, those with greater neural responses to true allergen had greater brain response to nocebo-induced itch, as well as greater placebo reduction of allergen-induced itch, which indicates overall modulation of itch sensation.27 Reduced responses in similar brain areas were associated with acupuncture-induced pruritic dampening in patients with AD.29 Such findings provide support for the role of expectations and psychological influence on itch perception. Although placebo and nocebo suggestions can influence itch sensation, studies have not found a corresponding measurable physiological skin effect.30

Allergic responses. The placebo response has been described as the “largest component of any allergy treatment.”31 The results of any allergy treatment comprises three components: a specific immunological or pharmacological effect, nonspecific effects, and a true placebo effect.31 Allergic responses can be influenced by nocebo effects from prior patient experiences, which influence accurate determination of drug reactions by affecting patient perception of symptoms. Nocebo responses to oral drug rechallenge efforts to confirm adverse reactions were mostly subjective, such as pruritus, with minor objective reactions like urticaria or erythema.32,33 Physician understanding of the nocebo phenomenon is important in this context to identify false positive responses and prevent subsequent potential erroneous treatment changes. More recently, open-label placebos have also been demonstrated to improve allergic rhinitis symptoms.34 Additionally, the level of information provided to patients about how placebos work did not affect symptom improvement. This finding suggests–remarkably–that placebo effects go beyond expectancy mechanisms previously described.

Implications for Dermatological Practice and Future Directions

As factors external to treatment mechanisms may play a significant role in the success or failure of dermatologic management,26 placebo and nocebo effects should be considered by dermatology providers, researchers, and patients. Dermatology research on any treatment should take placebo and nocebo outcomes under strong consideration when controlling study designs, such as by additionally comparing to no treatment when possible to estimate the placebo/nocebo effect, including open-label and closed-label designs, or hidden administration with patient consent. A hidden administration paradigm is most effective in controlling for placebo and nocebo effects by eliminating expectancies. This could be achieved by not informing participants when they are receiving the treatment or when the treatment is expected to work.26

With awareness among dermatology providers, greater focus can be placed on non-pharmacological strategies that may be applicable for optimizing most, if not all, dermatologic treatments, such as improving doctor-patient communication to ameliorate treatment adherence and expectations, and prevention of nocebo reactions by alleviating fear of adverse side effects. Establishing a trusting relationship is a key foundation for both nocebo prevention and placebo efficacy, as well as patient expectation and response; overly optimistic promises with lackluster outcomes may unintentionally induce a nocebo effect. Certain patients are more at-risk for nocebo effects, such as those with frequent concern over possible side effects, and could benefit from provider training in nocebo reduction via tactful disclosure.16 Detailing all potential risks and side effects of a treatment may not actually benefit a patient26 and simple word changes, such as using “discomfort” instead of “pain,” may be useful for nocebo minimization.35 Additional tips for clinicians can be found in Table 1.

Placebo responses can also impact the interpretation of treatment efficacy in clinical trials and identifying ways to minimize placebo responses in research may be important for increasing trial validity and reliability. In a systematic review and meta-analysis, researchers identified factors that influenced the placebo response in AD randomized controlled trials.36 They found that the use of concomitant topical therapy prescriptions, study duration of greater or equal to three months, and fewer treatment arms were associated with an increased placebo response for AD symptom reduction. Studies with a higher proportion of male patients and moderate to severe mean itch score at baseline were also associated with increased placebo responses. Additional tips for clinical trials can be found in Table 2.

Navigating the patient’s right to information alongside the possibility of nocebo resulting from disclosure is challenging. For patient safety and informed consent, it is important to distinguish whether reported side effects are true adverse results of treatment or nocebo, as well as to inform patients about life-threatening and serious side effects. Ethically, patients should be informed about the potential impact of their own expectations and other placebo/nocebo factors on their treatment, which may affect treatment choices. However, open-label trials have indicated that verbal suggestions for topical and transdermal itch-influencing treatments can influence itch expectations and alter self-reported itch, whether or not the subjects were aware of the placebo nature.37,38 Such open-label placebo effects have only a small body of related literature in dermatology yet could be promising for novel, ethical therapies harnessing placebo and nocebo effects, and consequently should be further investigated.34,37,39

Most studies on placebo and nocebo in dermatology have focused on AD, with notable results, yet minimal research has been performed on other common conditions, such as psoriasis, acne, or warts. Expanding research to include and compare a greater variety of skin and related atopic conditions could be a direction for future research. Greater standardization of placebo and nocebo induction mechanisms and other study design variables would help with generalizability and comparability of results. Predictors, for example, personality traits or psychological characteristics such as suggestibility and neurobiological mechanisms and processing of placebo and nocebo effects in dermatology should be further investigated.

Conclusion

Placebo and nocebo effects are old phenomena with new implications in research and clinical practice in every field of medicine, including dermatology. While research into placebo and nocebo effects has intriguing hypothetical practical implications for quality of life and treatment efficacy, more investigation is necessary to apply this knowledge clinically. The extrapolation of concepts of conditioning and suggestion into clinical practice and patient experience has not yet been detailed. Consequently, further determination of clinical translation and placebo or nocebo induction and maintenance efficacy is warranted.23 Once dermatologic placebo and nocebo effects are better characterized, there is immense potential for their manipulation for the benefit patients and their symptoms, such as improving treatments for those with chronic itch.

No funding has been received for this article.

Disclosure of Interest: Dr. Lio reports research grants/funding from Regeneron/Sanofi Genzyme, and Abbvie; is on the speaker’s bureau for Regeneron/Sanofi Genzyme, and Pfizer; reports consulting/advisory boards for UCB, Dermavant, Regeneron/Sanofi Genzyme, Dermira, Pfizer, LEO Pharmaceuticals, Abbvie, Kiniksa, Eli Lilly, Menlo Therapeutics, IntraDerm, Exeltis, Realm Therapeutics. The other authors report no conflicts of interest.

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19. Weisshaar E, Szepietowski J, Dalgard F, et al. European S2k Guideline on Chronic Pruritus.

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