Fabrizio Benedetti#

Short laudatio by Alexei Verkhratsky#


Fabrizio Benedetti has been working on the neurobiological mechanisms of the placebo effect for the last 15 years. He has contributed to clarify several aspects of the placebo effect, so that the placebo effect has passed from a nuisance in clinical research to an important model of mind-body interaction worthy of scientific investigation. The international impact of his research achievements is witnessed by the high standard of the international journal where he has published his papers and even more by the large number of invited Lectures that he has given at most prestigious international meetings. Last, but not least, he has acquired an important position by serving as consultant at the National Institute of Health in Bethesda, MD, USA.

Below there is a detailed account on his main achievements on the identification of several mechanisms of the placebo effect, as follows.

Role of endogenous opioids in placebo analgesia

Fabrizio Benedetti has described when and how placebo analgesia is mediated by the endogenous opioid systems and by other non-opioid systems. In particular, the placebo response can be induced through two mechanisms, expectation and conditioning. The former activates the endogenous opioids whereas the latter activates specific systems, depending on the drug used for conditioning (1,2,3,4).

Role of cholecystokinin (CCK) in placebo analgesia

He has also demonstrated that placebo analgesia is antagonized by endogenous CCK. In fact, on the basis of the anti-opioid action of CCK, it is possible to potentiate placebo analgesia with CCK—antagonists. Therefore, whereas opioids mediate placebo analgesia, CCK inhibits it (5,6).

Somatotopic organization of the endogenous opioid systems

If expectation of analgesia is directed only to a single part of the body and not to other parts, there is the activation of a specific opioid system which inhibits pain only in that part of the body. ln other words, there is a somatotopic organization of the placebo-activated endogenous opioids (7).

Effects of placebo on the respiratory centers and cardiovascular system

The placebo—activated endogenous opioids act not only on pain pathways, but also at the level of the respiratory centers, thus mimicking a typical side effect of opioids: respiratory depression. Recently, he has described a placebo respiratory depression which is mediated by endogenous opioids (8,9). Likewise, the placebo-activated opioid systems modulate the activity of the sympathetic system of the heart (10).

Clinical implications of placebo analgesia

The clinical importance of these results is twofold. First, he has shown that the interindividual variability of endogenous opioid activation is responsible, at least in part, for the response variability to analgesics (1 1). Second, if a placebo procedure is used in postoperative pain, it is possible to obtain a reduction of opioid intake (12).

Implications for clinical trials

He has developed new clinical trial designs in which the placebo effect can be studied without the administration of any placebo. This represents a potential tool for the assessment of new therapies in full agreement with the Declaration of Helsinki, which rejects the use of placebos in clinical trials (13,14,15).

Placebo effect and expectation in the motor system

Recently, he has used the approach described above in patients with Parkinson’s disease, in order to assess the effects of a placebo and expectation on the basal ganglia. To do this, he has recorded for the first time the activity of single neurons during a placebo response (16,17).

The nocebo effect

He has also studied the nocebo effect, which is opposite to placebo, and has shown that it is mediated by cholecystokinin. In addition, he has shown that the nocebo effect can be used as a model to understand anxiety-induced hyperalgesia (18,19,20)

Learning

More recently, his research has focused on the involvement of learning in placebo responsiveness, showing that placebo responses in different systems and medical conditions can be modulated by previous experience (21,22,23,24,25,26,27).

1. Benedetti F (1996) Pain 64, 535-4.
2. Benedetti F, Amanzio M (1997) Prog Neurobiol 52, 109-25.
3. Amanzio M, Benedetti F (1999) J Neurosci 19, 484-94.
4. Benedetti F etal. (2003) JNeurosci 23: 4315-4323.
5. Benedetti F etal. (1995) Lancet 346, 1231.
6. Benedetti F (1997) News Physiol Sci 12, 263-8.
7. Benedetti F et al. (1999) JNeurosci 19, 3639-48.
8. Benedetti F et al. (1998) Pain 75, 313-9.
9. Benedetti F et al. (1999) Eur JNeurosci 1 1, 625-31.
10. Pollo A et al. (2003) Pain, 102: 125-133.
ll. Amanzio M et al. (2001) Pain 90, 205-15.
12. Pollo A et al. (2001) Pain 93, 77-84.
13. Colloca L etal. (2004) Lancet Neurol 3: 679-684.
14. Finniss DG, Benedetti F (2005) Pain 114: 3-6.
15. Colloca L, Benedetti F (2005) Nature Rev Neurosci 6: 545-5 52.
16. Benedetti F etal. (2004) Nature Neurosci 7: 587-588.
17 Benedetti F etal. (2005) JNeurosci, 25: 10390-10402.
18. Benedetti et al. (2006) J Neurosci 26: 12014- 1 2022.
19. Benedetti etal. (2007) Neuroscience 147: 260-271.
20. Colloca L and Benedetti F (2007) Curr Opin Anaesthesiol 20: 435-439.
21. Benedetti Fetal. (2007) JNeur0sci 27: 1 1934-11939.
22. Price DD et al. (2008) Annu Rev Psychol 59: 565-590.
23. Benedetti F (2008) Annu Rev Pharmacol Toxicol 48: 33-60.
24. Colloca L et al. (2008) Pain, 136: 211-218.
25. Pollo A et al. (2008) Eur ./Neurosci, 28: 379-388.
26. Enck P et al. (2008) Neuron 59: 195-206.
27. Colloca L et al. (2008) Pain 139: 306-314.

The scientific achievements of Fabrizio Benedetti are also shown by the many invited lectures and plenary lectures, for example:
  • 2006 March, American Psichosomatic Society, Denver, CO, USA
  • 2006 March, Austrian Society of Neurology, Vienna
  • 2006 April, Global Summit on Neuropathic Pain, Berlin, Germany
  • 2006 June, Psychoneuroimmunolgy Research Society, Miami, FL, USA
  • 2006 June, American Headache Society, Los Angeles, CA, USA
  • 2006 July, Meeting of the German Psychological Society of Pain, Ulm, Germany
  • 2006 September, European Federation on Pain, Istanbul, Turkey
  • 2006 September, European Society of Neuro-oncology, Vienna
  • 2006 October, International Society of Psycho-oncology, Venice, Italy
  • 2006 December, American Epilepsy Society, San Diego, CA, USA
  • 2006 December, Pain in Dementia Symposium, Groningen, The Netherlands
  • 2007 March, Association of European Psychiatrists, Madrid, Spain
  • 2007 March, German Psychosomatic Society, Erlagen, Germany
  • 2007 April, Frontiers in Pain Research Lecture at McGill University, Montreal
  • 2007 June, International Congress of Neuropathic Pain, Berlin, Germany
  • 2007 July, International Narcotics Research Conference, Berlin, Germany
  • 2007 September, Italian Society of Neuroscience, Verona, Italy
  • 2007 November, Congress on Neuropathic Pain, Salt Lake City, UT, USA
  • 2007 November, Austrian Society of Biological Psychiatry, Vienna, Austria
  • 2007 November, International Symposium on Placebo, Tutzing, Germany
  • 2007 December, International Coalition on Neuropathic Pain Summit, Rome, Italy
  • 2008 April, Annual Meeting of the German Anesthesiology Society, Nuremberg, Germany
  • 2008 June, Meeting of the European Neurology Society, Nice, France
  • 2008 July, Brain and Cognition Symposium, Barcelona, Spain
  • 2008 August, l2th World Congress on Pain, Glasgow, UK
  • 2008 August, 25m Summer School on Brain Research, Amsterdam, The Netherlands
  • 2008 September, Neurodiab, Orvieto, Italy
  • 2008 September, European Academy of Craniomandibular Disorders, Zurich, Switzerland
  • 2008 October, Belgian Brain Council, Oostende, Belgium
  • 2008 November, Swiss Chapter of IASP, Bienne, Switzerland
  • 2009 January, Finnish Medical Association Annual Meeting, Helsinki, Finland
  • 2009 May, North American Conference of Integrative Medicine, Minneapolis, USA
  • 2009 May, AACP Annual Meeting, Wyboston, UK
  • 2009 June, German Psychological Society of Pain, Hamburg, Germany
  • 2009 September, European Federation of IASP Chapters, Lisbon, Portugal
  • 2009 October, World Congress of Neurology, Bangkok, Thailand

Fabrizio Benedetti has also served and is serving as consultant at the National Institute of Health (NIH), Bethesda, MD, USA, for the following projects:
  • 2000-2002 Co-chair of the Breakout Group of the NIH for the development of “Recommendations for research to further elucidate the nature of the placebo effect" Benedetti F, Czajkowski SM, Kitt CA, Stefanek M, Sternberg EM
  • (2002) In: HA Guess, A Kleinman, JW Kusek, LW Engel (Eds), The science of the placebo: Towards an interdiscqalinary research agenda. BMJ Books, pp 286-292.
  • 2003 Member of the Working Group of NIDA for planning a research agenda on the "Recovery of brain structure and function through behavioural treatments?
  • 2004 Member of the Brain—Body—Behavior Research Group of NCCAM for developing a strategic planning process for 2005-2009.
  • 2004 Member of the Task Force of NIMH on “Brain mechanisms in the placebo response".

Worthy of note are also the following:

Editorial Board Member

  • Pain (Elsevier: Amsterdam)
  • Seminars in Pain Medicine (Harcourt, Philadelphia,PA, USA): until 2003
  • Open Anesthesiology Journal (Bentharn, Oak Park, IL, USA) until 2008
  • Current Neuropharmacology (Bentham, Oak Park, IL, USA)

Organization of Congresses and Meetings
  • 2007 Co-organizer (together with Manfred Schedlowski, Germany and Paul Enck, Germany) of the international meeting "Mechanisms of Placebo/Nocebo Responses", Nov. 28-30, 2007, Tutzing, Germany
  • 2008 Co-organizer (together with Damien Finniss, Australia, Donald Price, USA, and Ron Kupers, Denmark) of the 12m World Congress on Pain Satellite Meeting "The placebo effect - Advances in research and implications for clinical trials and clinical practice", Aug. 14-15, 2008, Copenhagen, Denmark.

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