The nocebo effect is the opposite of the placebo effect. Nocebo effects occur when there is a suggested or expected negative medical outcome. The nocebo response can have effects on symptoms: in a study when doctors warned a group of patients that a procedure would be extremely painful, they experienced more pain than the group who were not given this warning. The nocebo response may also have effects on the course of disease: in a study of risk factors for heart disease, a group of women who believed they were prone to heart disease had an increase in death rate due to heart disease, 4 times greater than the group who had all the same risk factors except the belief they were prone to heart disease. Think sick, be sick. Might this effect occur in Huntington's?

Placebo Response in HD: Placebo effects, the positive response that occurs when a positive outcome is expected, is clearly present and of substantial size in HD. In the clinical trial for tetrabenazine, measures of chorea in people who got the placebo improved one-third as much as those who received the active drug [Savani AA 2007]. In the European ACR16 trial, preliminary reports suggest a similarly sized placebo response in measures of voluntary motor function. There is clearly sizeable placebo response -- at least in motor symptoms -- in HD.

Are there Nocebo Responses in HD? Though there have been no studies describing nocebo responses in HD, we should not assume they don't occur, or are not significant in this disease -- where the clear expectation is for negative outcome. If there are no studies in HD, what might we learn about nocebo effects from other illness situations that have been studied?

  • In Parkinson's disease (PD) performance on motor tests can be changed based on either positive or negative suggestions given by the doctor conducting the study [Enck P 2008]. In further studies it was shown that these responses have brain biology explanation; Dopamine activity in brain circuits changed in opposite directions based on whether the expected result was positive or negative [Benedetti F 2007]. A study on pain showed similar brain biology changes [Kong J 2008]. These studies show that cognitive processes (positive or negative thinking) are capable of influencing brain function.
  • Illness symptoms and side effects can be triggered by suggestion: A study was performed looking just at side effects reported by migraine subjects who received only placebo in several different drug trials [Amanzio M 2009]. Within each trial those who received placebo had the particular side effects specific to the drug which had been studied -- or the side effects suggested as most likely. Not only were illness symptoms triggered by suggestion, they were also specific to the "illness" suggestion.
  • Anxiety and fear can increase the severity of nocebo illness response. In a study of pain response, the authors showed that anxiety significantly increased the severity of pain [Colloca L 2007].
  • "Think sick" has influence on disease outcome. In analysis of outcomes of women from the Framingham Heart Study who believed they were prone to heart disease: this group was 4 times more likely to die of heart disease than another group of women with the same heart disease risk factors [Olshansky B 2007]. The higher heart disease death rate tracked with their belief of illness. This observation was called "Think sick, be sick".

Editors Comments: By itself, Huntington's is a bad disease. But I wonder if negative expectations and attitudes -- those of families and of doctors -- contribute to worsening of symptoms and disease course.

  • First, I wonder about the power of words and attitudes: How often do doctors (many of whom are generalists without specific knowledge of HD or the status of HD research) tell HD families after an initial motor diagnosis or gene testing that "nothing can be done"? And in the same time frame set up a referral to social services to help plan for disability. Do doctors know that a full-fledged grief reaction lasting in the range of a year often occurs? Do they offer that treatments are/will be available to help manage many symptoms, and that early treatment is best? Do they, and genetic counselors, HD social workers and support group leaders provide education about clinical research that offers hope? These are things that can be done right now that can make a difference.
  • Next I wonder how nocebo responses affect both the use and outcome of tetrabenazine treatment for chorea in HD. For more than a generation it has been drilled into patients and families that chorea is a minor symptom which causes little or no harm to HD patients or families. And instead of benefit, the greater emphasis is about the dangers of the drug. We might learn from clinical studies on propranolol (a drug used mostly for heart disease) that show the larger component of side effects experienced, including depression, fatigue and sexual dysfunction (as noted in package inserts) is due to suggestion that these side effects will occur [Ko DT 2002]. Of course there are "real" side effects caused by tetrabenazine, but isn't it highly probable there are additional, and probably significant nocebo effects for this drug as well?
  • And finally I wonder about gene testing for the asymptomatic. Authors of a recent genomic policy study raise concerns about the potential for detrimental nocebo responses based on genomic information -- and the concerns they discuss are for diseases that have a much lower expectation of sickness than HD [Haga SB 2009]. Further, investigators from the Pharos study of HD "at risk" individuals concluded that preservation of hope was an important motivation for those who don't test [Quaid KA 2008]. How important is this "hope" factor for the premanifest? Due to nobebo effects might illness factors be greater (at least in a sub-population of individuals) in those who test than those who don't?
  • Though it would be hard to unravel the effects of nocebo response and true disease response in HD, it seems to me that a careful look at HD observational trials (PHAROS, PREDICT and COHORT) might shed some light on these issues. If there is a nocebo response after motor diagnosis or following gene testing, it is vitally important to define it and provide appropriate and ongoing treatments and support for individuals and families in both groups.

References

Savani AA, Login IS. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2007 Mar 6;68(10):797; author reply 797. PubMed abstract

Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron. 2008 Jul 31;59(2):195-206. doi: 10.1016/j.neuron.2008.06.030. PubMed abstract

Benedetti F, Lanotte M, Lopiano L, Colloca L. When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience. 2007 Jun 29;147(2):260-71. Epub 2007 Mar 26. PubMed abstract

Kong J, Gollub RL, Polich G, Kirsch I, Laviolette P, Vangel M, Rosen B, Kaptchuk TJ. A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci. 2008 Dec 3;28(49):13354-62. doi: 10.1523/JNEUROSCI.2944-08.2008. PubMed abstract

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):261-9. doi: 10.1016/j.pain.2009.07.010. Epub 2009 Sep 24. PubMed abstract

Colloca L, Benedetti F. Nocebo hyperalgesia: how anxiety is turned into pain. Curr Opin Anaesthesiol. 2007 Oct;20(5):435-9. PubMed abstract

Olshansky B. Placebo and nocebo in cardiovascular health: implications for healthcare, research, and the doctor-patient relationship. J Am Coll Cardiol. 2007 Jan 30;49(4):415-21. Epub 2007 Jan 16. PubMed abstract

Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002 Jul 17;288(3):351-7. PubMed abstract

Haga SB, Warner LR, O'Daniel J. The potential of a placebo/nocebo effect in pharmacogenetics. Public Health Genomics. 2009;12(3):158-62. doi: 10.1159/000189628. Epub 2009 Feb 10. PubMed abstract

Quaid KA, Sims SL, Swenson MM, Harrison JM, Moskowitz C, Stepanov N, Suter GW, Westphal BJ. Living at risk: concealing risk and preserving hope in Huntington disease. J Genet Couns. 2008 Feb;17(1):117-28. Epub 2007 Oct 18. PubMed abstract