Placebo and its evil twin, nocebo

Abstract

According to Merriam-Webster.com, nocebo is defined as “a harmless substance that when taken by a patient is associated with harmful effects due to negative expectations or the psychological condition of the patient.”1Merriam-Webster. Nocebo. Available at: http://www.merriam-webster.com/dictionary/nocebo. Accessed February 14, 2016.Google Scholar Although placebos and the placebo effect are well known, little has been written about nocebos and the accompanying nocebo effect. Nocebos and the nocebo effect are, however, game changers, both in regard to approaching and treating patients, as well as to research. The unanticipated outcomes of both placebos and nocebos are often referred to as expectation effects—that people’s expectations may strongly affect their response to pain and physical healing. This idea was suggested more than 60 years ago by Dr. Henry Bleecher, named the first endowed chair of anesthesiology in the United States.2Massachusetts General Hospital; Anesthesia, Critical Care and Pain Medicine. Anesthesia history milestones. Available at: http://www.massgeneral.org/anesthesia/about/history.aspx. Accessed February 14, 2016.Google Scholar, 3Beecher H.K. The powerful placebo.JAMA. 1955; 159: 1602-1606Crossref PubMed Scopus (1183) Google Scholar Achieving a measurable objective response to placebos outside of clinical trial settings has been challenged, although there may be a therapeutic response during the treatment of pain in a nonresearch situation.4Hróbjartsson A. Gøtzsche P.C. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.N Engl J Med. 2001; 344 ([published correction appears in N Engl J Med. 2001;345(4):304]): 1594-1602Crossref PubMed Scopus (1262) Google Scholar Overall, it has been suggested that the placebo effect operates predominantly on signs and symptoms but cannot change a biological state or disease.5Miller F.G. Colloca L. The legitimacy of placebo treatments in clinical practice: evidence and ethics.Am J Bioeth. 2009; 9: 39-47Crossref Scopus (121) Google Scholar Placebos cannot cure cancer or trigeminal neuralgia, but they can induce a physiological response. This lack of a genuine effect on a disease calls into question the ethical use of placebos as bona fide treatment options. Of interest to dentists, the first scientific proof of the physiological origin for the placebo effect came to light in a third-molar extraction study published almost 40 years ago.6Levine J.D. Gordon N.C. Fields H.L. The mechanism of placebo analgesia.Lancet. 1978; 2: 654-657Abstract PubMed Scopus (764) Google Scholar The authors stated, “These data are consistent with the hypothesis that endorphin release mediates placebo analgesia for dental postoperative pain.”6Levine J.D. Gordon N.C. Fields H.L. The mechanism of placebo analgesia.Lancet. 1978; 2: 654-657Abstract PubMed Scopus (764) Google Scholar Today, researchers are continuing to explore the association between neuropathic pathways and the placebo effect. A genomic effect called the placebome has been added to the discussion, and it could explain why certain people—placebo responders—are more susceptible than others.7Hall K.T. Loscalzo J. Kaptchuck T.J. Genetics and the placebo effect: the placebome.Trends Mol Med. 2015; 21: 285-294Abstract Full Text Full Text PDF Scopus (165) Google Scholar The placebo effect, it turns out, is a very appropriate term. The word placebo comes from Latin, meaning “I will please.” The etymology of this word may be related to a practice during medieval times when mourners were hired to chant during vespers for the dead. This practice was considered by many to be disingenuous, and the hired mourners were called placebos. Nocebo, from Latin meaning “I will harm,” was initially suggested by Walter Kennedy in 1961.8Kennedy W.P. The nocebo reaction.Med World. 1961; 95: 203-205PubMed Google Scholar The terms nocebo and nocebo reaction were chosen to contrast with and be the direct opposite of the then already known placebo phenomenon. Understanding and accurately anticipating both placebo and nocebo effects are being intensely studied for 2 reasons: to avoid unwanted outcomes and so these effects can be used for therapeutic purposes. It is clear that caregivers can enhance patients’ experiences by anticipating or even being able to use a placebo or nocebo response. Placebos appear in different guises, such as pharmacologic, physical, or psychological, and so may nocebos. Although a placebo response is associated with expectations of rewards and relief of anticipated noxious effects, a nocebo response will enhance undesirable expectations. Thus, patients expecting adverse effects from a medication or a procedure may report actually having these adverse effects even when they receive nonactive intervention. Even the informed consent process itself may result in adverse experiences.9Colloca L. Miller F.G. The nocebo effect and its relevance for clinical practice.Psychosom Med. 2011; 73: 598-603Crossref PubMed Scopus (266) Google Scholar, 10Wells R.E. Kaptchuck T.J. To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent.Am J Bioeth. 2012; 12: 22-29Crossref PubMed Scopus (175) Google Scholar Alerting patients to possible pain associated with administering local anesthetic injections has been shown to produce more adverse reactions than if patients were told that they may feel only slight discomfort.11Varelmann D. Pancaro C. Cappiello E.C. Camann W.R. Nocebo-induced hyperalgesia during local anesthetic injection.Anesth Analg. 2010; 110: 868-870Crossref PubMed Scopus (154) Google ScholarCaregivers can enhance patients' experiences by anticipating or even being able to use a placebo or nocebo response. Caregivers can enhance patients' experiences by anticipating or even being able to use a placebo or nocebo response. The magnitude of a nocebo effect on pain, as calculated in a meta-analysis, is similar to that described for a placebo effect.12Petersen G.L. Finnerup N.B. Colloca L. et al.The magnitude of nocebo effects in pain.Pain. 2014; 155: 1426-1434Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 13Vase L. Riley 3rd, J.L. Price D.D. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia.Pain. 2002; 99: 443-452Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar The extent of both effects is greater when prompted by a combination of verbal suggestions and conditioning than when prompted by verbal suggestions alone. However, verbal suggestions alone have been documented as potentially inducing a nocebo effect—worsening of pain—that was greater than active analgesic medication.14Bingel U. Wanigasekera V. Wiech K. et al.The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opoid remifentanil.Sci Transl Med. 2011; 3: 70ra14Crossref PubMed Scopus (502) Google Scholar Until acceptable methods for identifying high placebo and nocebo responders exist, results from clinical trials elucidating pain management or pain relief may be questioned. Several different theories have been put forth on the mechanism of both placebo and nocebo effects that need to be addressed in trial designs.15Vase L. Amanzio M. Price D.D. Nocebo vs. placebo: the challenge of trial design in analgesia research.Clin Pharmocol Ther. 2015; 97: 143-150Crossref Scopus (39) Google Scholar Suffice it to say, the specific wording and process of giving informed consent need to be highly standardized for every trial participant. For example, different placebo and nocebo responses may be elicited by changing the wording in a consent from “you will receive a very effective pain medication”—certainty—to “the pill you are receiving may be an effective pain medication or a placebo”—uncertainty. Nocebo response in clinical practice has not been adequately studied. But, it is clear that such an effect exists outside of experimental situations and clinical trials. How can a nocebo response be minimized when, for example, we administer a local anesthetic? That is unclear, but negative information about what a patient will feel—expectations—should be minimized. Rather than pointing out how painful an injection will be, the patient should be told that they may feel only some discomfort. As conditioning plays a big role, it would be beneficial, if possible, to start treatment with less pain-inducing procedures rather than have a patient associate a visit to the dentist with a painful experience. Invalidating patients’ preferences and values may also induce a nocebo response, and this effect should be recognized when communicating with patients.16Greville-Harris M. Dieppe P. Bad is more powerful than good: the nocebo response in medical consultations.Am J Med. 2015; 128: 126-129Abstract Full Text Full Text PDF Scopus (50) Google Scholar Today, the interplay between psychological, physiological, genetic, and other influences that could explain the placebo and nocebo effects is a burgeoning area of research that will directly influence patient care. A better understanding and appreciation of these phenomena will certainly make us better and more successful health care providers. Dr. Glick is a professor and the William M. Feagans Chair, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY. He also is the editor of The Journal of the American Dental Association. Informed consentThe Journal of the American Dental AssociationVol. 147Issue 7PreviewAs a dental educator, the April JADA editorial “Placebo and Its Evil Twin, Nocebo” (Glick M. JADA. 2016;147[4]:227-228) was much appreciated. Every clinical dentist intuitively understands that some verbiage that slipped out during dental school is best avoided, such as alerting patients that a procedure may be “painful.” As reported, patients have better experiences when different words, such as uncomfortable, are used. What about simply avoiding potentially distressing consent commentary about possible impending discomfort or complications? Full-Text PDF