bmj.com Rapid Responses for Spiegel, 329 (7472) 927-928

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EDITORIALS:
David Spiegel
Placebos in practice
BMJ 2004; 329: 927-928 [Full text]

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Rapid Responses published:

Placebo or effective therapetic relationship?: Amanda Connell (22 October 2004)

Beliefs in Practice: Christine Bundy (22 October 2004)

Placebo use is well known, placebo effect is not: Toke S. Barfod (22 October 2004)

Placebo explained: Consciousness causal to health.: S�ren Ventegodt, Joav Merrick (22 October 2004)

Placebos in practice. Our point of view: Luis G. Del Sol - Padr�n, Alfredo D. Espinosa-Brito, Benigno Figueiras-Ramos, Ra�l E. Nieto-Cabrera and Alfredo A. Espinosa-Roca (23 October 2004)

Placebos in pain: Nicholas D. Moore (24 October 2004)

Placebo Analgesia: Peter KK Au-Yeung (25 October 2004)

A biological mechanism for the placebo effect: Dylan Evans (26 October 2004)

Using a Placebo may be unethical: David Brookman (27 October 2004)

Placebos in Practice and Research: Disentangling Medical Paradoxes: Zelda Di Blasi, David Reilly, Consultant Physician, Centre for Integrative Care, Glasgow Homeopathic Hospital, 1053 Great Western Road, Glasgow (28 October 2004)

Placebos in practice: conscious and unconscious use: Magi Farre, Yolanda Alvarez, Alexis Rodr�guez (HUVH), Sergio Abanades (31 October 2004)

Undocumented editorial on placebos: Peter C G�tzsche, Asbj�rn Hr�bjartsson (5 November 2004)

Homeopathy?: Alfred P J Lake (5 November 2004)

Re: Placebos in practice: conscious and unconscious use: Peter KK Au-Yeung (6 November 2004)

Placebo is effective and it differs from sham drugs or "inadrugs": Markku Partinen (17 November 2004)

Placebo or effective therapetic relationship? 22 October 2004

Amanda Connell,
lecturer in physiotherapy
university of limerick
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Re: Placebo or effective therapetic relationship?

In physiotherapy, where the "science" underpinning our therapeutic interventions is often nebulous, if not absent, the placebo effect is often cited as equally effective as interventions. This is not to say that physiotherapy is ineffective but, possibly, the more difficult research questions about the effect of the interaction between patients and therapists have not been fully investigated. The "art" of physiotherapy is in convincing patients to do something that they either do not want to do or think that they cannot do. Maybe all healthcare professions could benefit from expanding their definition of evidence based practice to include "arts" research.
Hinman RS; Crossley KM; McConnell J; Bennell KL Does the application of tape influence quadriceps sensorimotor function in knee osteoarthritis? Rheumatology 2004 Mar; 43 (3),pp. 331-6
Hondras MA; Linde K; Jones AP Manual therapy for asthma The Cochrane Library (Oxford), 2004 n.2
Van der Windt DAW; Van der Heijden GJM; Van den Berg SGM; Ter Riet G; De Winter AF; Bouter LM Ultrasound therapy for acute ankle sprains The Cochrane Library (Oxford), 2004 n.2
Competing interests: None declared

Beliefs in Practice 22 October 2004

Christine Bundy,
Senior Lecturer in Psychological Medicine/Health Psychology
University of Manchester, Medical School
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Re: Beliefs in Practice

I am pleased to see the issue of placebos raised in the BMJ again. I am also disappointed that there seems to be little scientific appetite for research into the mechanisms of placebo. Perhaps this is because it is complex research involving many difficult to control factors (ie clinicians' and patients' psychology).
There are many important questions raised around placebos, for example, is there a dose response to placebo; do beliefs about the 'real' effects held by clinicians influence the patients' beliefs? Is anyone working in this area?
We hold an annual student symposium in Manchester around the evidence base for Complementary and Alternative Medicines, the issue of placebo is one that interestes the students and by and large they are very open minded (ie appropriately critical) about the potential of placebo. By the time the same students qualify they appear to have changed their beliefs and refer to it as an unreal effect. What happens along the way, do they re-appraise the evidence, do they conduct their own research? I think not. More likely they adopt a popular prejudice held by many of their colleagues.
The effect of placebo is real, the fact that we cannot explain the mechanism yet makes it no less real. Stop exposing your unsophisticated medical model that views anything that happens in a person's head as 'unreal' it's tiresome!
Competing interests: None declared

Placebo use is well known, placebo effect is not 22 October 2004

Toke S. Barfod,
Clinical researcher
Department of Infectious Diseases, Rigshospitalet. 2100 Copenhagen, Denmark.
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Re: Placebo use is well known, placebo effect is not

Dear Sirs
In their otherwise excellent paper regarding the use of placebos in clinical practice(1), Nitzan and Lichtenberg state that they were unable to find more than one other study(2) on the use of placebos in a clinical context. I kindly wish to draw the attention to a number of similar studies(3-10).
In the accompanying editorial(11), David Spiegel rightly points out that the famous Cochrane review on the placebo effect(12) probably underestimated the placebo effects of treatments. Spiegel gave some methodological explanations for this underestimation, but failed to mention a much more important reason. A very fundamental problem with the Cochrane review, as mentioned in three letters by Lilford & Braunholtz, Kuppers and Shrier(13), is that the included studies are done in a setting completely different from the situation in clinical practice. The included studies are three-armed studies, where patients are randomly allocated to a supposedly active treatment, to a placebo or to no treatment. The placebo effect is then defined as the difference in effect in the patients receiving placebo as compared to those receiving no treatment. Obviously, neither the patient nor the physician in such a trial will have any substantial belief in the (placebo-) treatment or consider it particularly meaningful. And obviously this situation is completely different from clinical practice, where the patient and/or the physician believes in the therapeutic powers of a treatment, which they most likely consider meaningful. The difference between randomized trials and clinical practice is always a problem, but much more so in the study of placebos and related phenomena(14;15). In my view, this one of the main reasons why the Cochrane review does not exclude the possibility of strong placebo effects in clinical practice.
Regards,
Toke S. Barfod. Clinical researcher. Copenhagen.
Reference List
1. Nitzan U,.Lichtenberg P. Questionnaire survey on use of placebo. BMJ 2004;329:944-6.
2. Goodwin JS, Goodwin JM, Vogel AV. Knowledge and use of placebos by house officers and nurses. Ann Intern Med 1979;91:106-10.
3. Goldberg RJ, Leigh H, Quinlan D. The current status of placebo in hospital practice. Gen.Hosp.Psychiatry 1979;1:196-201.
4. Gray G,.Flynn P. A survey of placebo use in a general hospital. Gen.Hosp.Psychiatry 1981;3:199-203.
5. Thomson RJ,.Buchanan WJ. Placebos and general practice: attitudes to, and the use of, the placebo effect. N.Z.Med.J. 1982;95:492-4.
6. Shapiro AK,.Struening E. Defensiveness in the definition of placebo. Compr.Psychiatry 1973;14:107-20.
7. Hofling CK. The place of placebos in medical practice. G.P. 1955;11:103-7.
8. Hrobjartsson A,.Norup M. The use of placebo interventions in medical practice--a national questionnaire survey of Danish clinicians. Eval.Health Prof. 2003;26:153-65.
9. Berger JT. Placebo medication use in patient care: a survey of medical interns. West J.Med 1999;170:93-6.
10. Lynoe N, Mattsson B, Sandlund M. The attitudes of patients and physicians towards placebo treatment--a comparative study. Soc.Sci.Med 1993;36:767-74.
11. Spiegel D. Placebos in medicine. BMJ 2004;329:927-8.
12. Hrobjartsson A,.Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N.Engl.J.Med 2001;344:1594-602.
13. Is the placebo powerless? (Correspondence). NEJM 2001;345:1276-9.
14. Olesen F,.Barfod TS. The concept of placebo and general practice - is it time to avoid the word placebo? Editorial. Scand.J.Prim.Health Care 2000;18:193-4.
15. Barfod TS. Kan randomisering skabe bias? Statusartikel [Can randomization create bias? State-of-the-art]. Ugeskr.Laeger 2001;163:7025-6.
Competing interests: None declared

Placebo explained: Consciousness causal to health. 22 October 2004

S�ren Ventegodt,
Medical director
1The Quality of Life Research Center, Teglg�rdstr�de 4-8, DK-1452 Copenhagen K, Denmark,
Joav Merrick
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Re: Placebo explained: Consciousness causal to health.

EDITOR---David Spiegel [1] raises the important question how placebo works. In holistic or consciousness based medicine as we like to call it, we use the induction of changes in the patients consciousness as medicine. What this emerging branch of medical science has been doing during the last two decades is to identify several aspects of consciousness � emotional, cognitive, relational - which from large quantitative studies[2 -12] are known to be highly relevant to health and healing inorder to cultivate these into an efficient toolbox for use in the medical clinic[13 -15].
Instead of giving tablets of like calciumcarbonate or clean salt water injections and letting the patient believe that the healing power is in the tablet or syringe [16], we admit openly to our patients that this medicine works directly though the consciousness of the patient. We try to explain to our patients, as well as we can, according to the holistic theories, even with cancer [17] or other diseases, why this shift in consciousness (that we try to induce) will lead to a positive change in the patient�s state of health [18-25].
If this gives meaning to the patient, it will work, but if the patient is unwilling to work with this explanation, is does not work. This is the ultimate use of placebo. As we have described in many cases now, the patients will often get better [26-31], sometimes even be completely cured, as explained by the holistic process theory of healing [32].
We usually explain the connection between consciousness and health through the concept of global quality of life [33-35]. We therefore also call this open use of placebo for scientific holistic medicine [36-38] or �quality of life as medicine� [39-41]. A more accurate explanation of the connection between health and consciousness are given by the life mission theories [42-48]. We now seem to have collected sufficient empirical evidence to conclude that consciousness really is causal to health in many cases; in four studies including 11.000 Danes examined with the comprehensive, validated questionnaire SEQOL [49], we found that QOL, health and ability primarily are determined by consciousness[12].
We hope that the medical scientific community will engage in the discussion of these results, and that this new line of scientific holistic medicine (�the new medicine�) and its clinical practise will be used by many physicians and help many patients.
AFFILIATION
S�ren Ventegodt, MD, is a general practitioner and the director of the Quality of Life Research Center in Copenhagen, Denmark. E-mail: ventegodt@livskvalitet.org Website: www.livskvalitet.org/
Joav Merrick, MD, DMSc is professor of child health and human development, director of the National Institute of Child Health and Human Development and the medical director of the Division for Mental Retardation, Ministry of Social Affairs, Jerusalem, Israel. E-mail: jmerrick@internet-zahav.net. Website: www.nichd-israel.com
REFERENCES
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2. Ventegodt S. Sex and the quality of life in Denmark. Arch Sex Behaviour 1998;27(3):295-307.
3. Ventegodt S. A prospective study on quality of life and traumatic events in early life � 30 year follow-up. Child Care Health Dev 1998;25(3):213-21.
4. Ventegodt S, Merrick J. Long-term effects of maternal smoking on quality of life. Results from the Copenhagen Perinatal Birth Cohort 1959- 61. ScientificWorld Journal 2003;3:714-20.
5. Ventegodt S, Merrick J. Long-term effects of maternal medication on global quality of life measured with SEQOL. Results from the Copenhagen Perinatal Birth Cohort 1959-61. ScientificWorldJournal 2003;3:707-13.
6. Ventegodt S, Merrick J. Psychoactive drugs and quality of life. ScientificWorldJournal 2003;3:694-706.
7. Ventegodt S, Merrick J. Lifestyle, quality of life and health. ScientificWorldJournal 2003;3:811-25.
8. Ventegodt S. Livskvalitet I Danmark. Quality of life in Denmark. Results from a population survey. [partly in Danish] Copenhagen: Forskningscentrets Forlag, 1995.
9. Ventegodt S. Livskvalitet hos 4500 31-33 �rige. The Quality of Life of 4500 31-33 year-olds. Result from a study of the Prospective Pediatric Cohort of persons born at the University Hospital in Copenhagen. [partly in Danish] Copenhagen: Forskningscentrets Forlag, 1996.
10. Ventegodt S. Livskvalitet og omst�ndigheder tidligt i livet. The quality of life and factors in pregnancy, birth and infancy. Results from a follow-up study of the Prospective Pediatric Cohort of persons born at the University Hospital in Copenhagen 1959-61. [partly in Danish] Copenhagen: Forskningscentrets Forlag, 1995.
11. Ventegodt S. Livskvalitet og livets store begivenheder. The Quality of Life and Major Events in Life. [partly in Danish] Copenhagen: Forskningscentrets Forlag, 2000.
12. Ventegodt S, Flensborg-Madsen T, Andersen NJ, Nielsen M, Morad, M, Merrick J. Global quality of life (QOL), health and ability are primarily determined by our consciousness. Research findings from Denmark 1991-2004. Accepted by Social Indicator Research 2004
13. Ventegodt S, Morad M, Andersen NJ, Merrick J. Clinical holistic medicine Tools for a medical science based on consciousness. ScientificWorldJournal 2004;4:347-361.
14. Ventegodt S, Morad M, Merrick J. Clinical holistic medicine: Holistic pelvic examination and holistic treatment of infertility. ScientificWorldJournal 2004;4:148-158.
15. Ventegodt S, Morad M, Merrick J. Clinical holistic medicine: Classic art of healing or the therapeutic touch. ScientificWorldJournal 2004;4:134-147.
16. Klopfer B. Psychological Variables in Human Cancer. J Project Tech 1957;21(4):331-40.
17. Ventegodt S, Morad M, Merrick J. Clinical holistic medicine: Induction of Spontaneous Remission of Cancer by Recovery of the Human Character and the Purpose of Life (the Life Mission). ScientificWorldJournal 2004;4:362-77.
18. Ventegodt S, Andersen NJ, Merrick J. Quality of life philosophy: when life sparkles or can we make wisdom a science? ScientificWorldJournal 2003;3:1160-3.
19. Ventegodt S, Andersen NJ, Merrick J. QOL philosophy I: Quality of life, happiness, and meaning of life. ScientificWorldJournal 2003;3:1164- 75.
20. Ventegodt S, Andersen NJ, Kromann M, Merrick J. QOL philosophy II: What is a human being? ScientificWorldJournal 2003;3:1176-85.
21. Ventegodt S, Merrick J, Andersen NJ. QOL philosophy III: Towards a new biology. ScientificWorldJournal 2003;3:1186-98.
22. Ventegodt S, Andersen NJ, Merrick J. QOL philosophy IV: The brain and consciousness. ScientificWorldJournal 203;3:1199-1209.
23. Ventegodt S, Andersen NJ, Merrick J. QOL philosophy V: Seizing the meaning of life and getting well again. ScientificWorldJournal 2003;3:1210-29.
24. Ventegodt S, Andersen NJ, Merrick J. QOL philosophy VI: The concepts. ScientificWorldJournal 2003;3:1230-40.
25. Merrick J, Ventegodt S. What is a good death? To use death as a mirror and find the quality in life. BMJ. Rapid Responses, 31 October 2003.
26. Ventegodt S, Morad M, Merrick J. Clinical holistic medicine: The �new medicine�, the multi-paradigmatic physician and the medical record. ScientificWorldJournal 2004;4:273-85.
27. Ventegodt S, Morad M, Kandel I, Merrick J. Clinical holistic medicine: Social problems disguised as illness. ScientificWorldJournal 2004;4:286-94.
28. Ventegodt S, Morad M, Merrick J. Clinical holistic medicine: Holistic treatment of children. ScientificWorldJournal 2004;4:581-8.
29. Ventegodt S, Morad M, Kandel I, Merrick J. Clinical holistic medicine: Problems in sex and living together. ScientificWorldJournal 2004;4:562-70.
30. Ventegodt S, Morad M, Hyam E, Merrick J. Clinical holistic medicine: Holistic sexology and treatment of vulvodynia through existential therapy and acceptance through touch. ScientificWorldJournal 2004;4:571-80.
31. Ventegodt S, Flensborg-Madsen T, Andersen NJ, Morad M, Merrick J. Clinical holistic medicine: A Pilot on HIV and Quality of Life and a Suggested treatment of HIV and AIDS. ScientificWorldJournal 2004;4:264-72.
32. Ventegodt, S., Andersen, N.J., Merrick, J. (2003) Holistic Medicine III: The holistic process theory of healing. ScientificWorldJournal 3:1138-1146
33. Ventegodt S, Merrick J, Andersen NJ. Quality of life theory I. The IQOL theory: An integrative theory of the global quality of life concept. ScientificWorldJournal 2003;3:1030-40.
34. Ventegodt S, Merrick J, Andersen NJ. Quality of life theory II. Quality of life as the realization of life potential: A biological theory of human being. ScientificWorldJournal 2003;3:1041-9.
35. Ventegodt S, Merrick J, Andersen NJ. Quality of life theory III. Maslow revisited. ScientificWorldJournal 2003;3:1050-7.
36. Ventegodt S, Andersen NJ, Merrick J. Holistic medicine: Scientific challenges. ScientificWorldJournal 2003;3:1108-16.
37. Ventegodt S, Andersen NJ, Merrick J. Holistic Medicine II: The square-curve paradigm for research in alternative, complementary and holistic medicine: A cost-effective, easy and scientifically valid design for evidence based medicine. ScientificWorldJournal 2003;3: 1117-27.
38. Ventegodt S, Andersen NJ, Merrick J. Holistic Medicine IV: Principles of the holistic process of healing in a group setting. ScientificWorldJournal 2003;3:1294-1301.
39. Ventegodt S, Merrick J, Andersen NJ. Quality of life as medicine. A pilot study of patients with chronic illness and pain. ScientificWorld Journal 2003;3:520-32.
40. Ventegodt S, Merrick J, Andersen NJ. Quality of life as medicine II. A pilot study of a five day �Quality of Life and Health� cure for patients with alcoholism. ScientificWorld Journal 2003;3:842-52.
41. Ventegodt S, Clausen B, Langhorn M, Kroman M, Andersen NJ, Merrick J. Quality of Life as Medicine III. A qualitative analysis of the effect of a five days intervention with existential holistic group therapy or a quality of life course as a modern rite of passage. ScientificWorldJournal 2004;4:124-133.
42. Ventegodt S, Andersen NJ, Merrick J. Editorial: Five theories of human existence. ScientificWorldJournal 2003;3:1272-6.
43. Ventegodt S. The life mission theory: A theory for a consciousness- based medicine. Int J Adolesc Med Health 2003;15(1):89-91.
44. Ventegodt S, Andersen NJ, Merrick J. The life mission theory II: The structure of the life purpose and the ego. ScientificWorldJournal 2003;3:1277-85.
45. Ventegodt S, Andersen NJ, Merrick J. The life mission theory III: Theory of talent. ScientificWorldJournal 2003;3:1286-93.
46. Ventegodt S, Merrick J. The life mission theory IV. A theory of child development. ScientificWorldJournal 2003;3:1294-1301.
47. Ventegodt S, Andersen NJ, Merrick J. The life mission theory V. A theory of the anti-self and explaining the evil side of man. ScientificWorldJournal 2003;3:1302-13.
48. Ventegodt S, Andersen NJ, Merrick J. The life mission theory VI: A theory for the human character. Accepted by ScientificWorldJournal 2004;4.
49. Ventegodt S, Henneberg EW, Merrick J, Lindholt JS. Validation of two global and generic quality of life questionnaires for population screening: SCREENQOL & SEQOL. ScientificWorldJournal 2003;3:412-21.
Competing interests: None declared

Placebos in practice. Our point of view 23 October 2004

Luis G. Del Sol - Padr�n,
Assistant Professor of Internal Medicine
Hospital Dr. Gustavo Alderegu�a Lima, Ave 5 de Septiebre y Calle 51A, Cienfuegos 55 100, Cuba,
Alfredo D. Espinosa-Brito, Benigno Figueiras-Ramos, Ra�l E. Nieto-Cabrera and Alfredo A. Espinosa-Roca
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Re: Placebos in practice. Our point of view

Dear Editor:
Nowadays, the �classical� clinical method approach �for diagnosis and treatment-, is in crisis. Moreno attributes this situation to the inadequate relationship between doctor and patient, to the progressive process of specialization, and to the increasing confidence �by doctors and patients- in modern technology (1)
Decision making and therapeutics are the last step of the clinical method, going from the active contemplation to action, and from the identification and knowledge to transformation until it is permitted by science and individuality of each patient. (2) This stage has to combine the best available evidences (science) to solve each case and the best clinical expertise (art).
In the evidence based medicine era, �the placebo pleases modern doctors�, as we confirm reading the two interesting articles about �Placebos in practice� published in the last number of the BMJ. (3,4).
�Most of medicine used placebos at one time. Medicine in the 20th century was supposed to end this�. (3) Then, why occurred it? We can assure that the scientific-technological advances in the last 60 years mainly changed the technique, but not the clinics. Feinstein named �iatrotherapy�, to all actions that we as physicians do with the patients, besides our �technical� activity. (5)
We think that the use of placebos in clinical practice depends on several factors. Among them, we want to emphasize in two ones.
1. Different models of doctor-patient relationships. We can recognized at least four:
a) The doctor as a scientist, who is only evidence based in his practice, and not involved in ethical and moral evaluations of the patients. b) The doctor as a priest, where the patient recognizes not only the doctor�s expertise but, with a great emphasis, he (she) as a moral authority with little participation of the patients in all decisions. c) The doctor as an agreement maker, that stresses on rights and obligations of each part, preventng claims. d) The doctor as a patient comrade, as a true physician, where both are partners with the same goal: to eliminate the illness and to recovery health, with great participation of the patients in all decisions. This models preserves confidence, safety, dignity and mutual respect. This is the model that all of us wishes for our relatives and ourselves.
We consider that placebo is only possible in cases of b) and d).
In April 2004, we interviewed 73 (27.3%) out of 267 inpatients at the Hospital Dr. Gustavo Alderegu�a Lima, who were admitted in clinical and surgical wards. They were randomized selected. Only one refused to participate. The objective was to know the qualities that our inpatients expected in their doctors. We made only one question: What are the main qualities that you expect to find in your doctors?
The first five answers were: Pleasing 67 (91,8%), Experienced 61 (83,6%), Listener 37 (50,7%), Frank, open 30 (41,1%), Respectful 30 (41,1%).
So, we agree that �the placebo effect, thought of as the result of the inert pill, can be better understood as an effect of the relationship between doctor and patient. Adding the doctor's caring to medical care affects the patient's experience of treatment, reduces pain, and may affect outcome� (3), especially when there is a good relationship between them, and we, as doctors, fulfilled their expectations. (6)
2. The �type� of the patient condition (disease or injury). Lolas identified: (7)
a) Sudden an catastrophic, life threating b) Acute, unexpected, with interruption of normal life c) Chronic disorders, almost always permanent, not life threating in short time d) Daily, minor distress, trivial, frequently related to social factors
Of course, placebos could be indicated only in some c) and d) cases. This assertion is in concordance with Nitzan and Lichtenberg, who reported that �the medical conditions for which the placebos were used included in their survey: anxiety, pain (including abdominal), agitation, vertigo, sleep problems, asthma, contractions in labour, withdrawal from recreational drugs, and angina pectoris (when the blood pressure was too low to allow for vasodilators). The stated value as a diagnostic tool�, referred by them, �was to distinguish organic from psychogenic or simulated arthralgia, seizure disorder, and abdominal or other pain�.(4)
Finally, we also agree that �the role of placebo treatment, its mechanisms, and its ethics need to be the subject of wider medical education and debate� (4)
Luis Gustavo Del Sol-Padr�n, MD, Assistant Professor Alfredo D. Espinosa-Brito, MD, PhD, Professor Benigno Figueiras- Ramos, MD, Instructor Ra�l E. Nieto-Cabrera, MD Alfredo A. Espinosa-Roca, MD, Asistant Professor
Department of Internal Medicine Hospital Dr. Gustavo Alderegu�a Lima Cienfuegos, Cuba.
References
1. Moreno MA. El arte y la ciencia del diagn�stico m�dico. Principios seculares y problemas actuales. La Habana: Cient�fico-T�cnica, 2001. 2. Espinosa A. Medicina Interna, �qu� fuiste, qu� eres, qu� ser�s?� Rev Cubana Med 1999;38(1):79-90. 3. Spiegel D. Placebos in practice (editorial). BMJ 2004: 329:927-928. 4. Nitzan U, Lichtenberg P. Questionnaire survey on use of placebo. BMJ 2004 329: 944-946. 5. Feinstein AR. Clinical epidemiology. Philadelphia:. WB Saunders, 1985. 6. Culliford L. Spirituality and clinical care (editorial) BMJ 2002;325:1434-1435 7. Lolas F. M�s all� del cuerpo. Santiago de Chile: Andr�s Bello, 1997.
Competing interests: None declared

Placebos in pain 24 October 2004

Nicholas D. Moore,
Professor of clinical pharmacology
Universit� Victor Segalen, 33076 Bordeaux
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Re: Placebos in pain

you rightly state that it is not because pain is relieved by placebo that it is not real. I would go one step further: as one of my teachers told me almost 30 years ago (Pr Raymond Villey, in Caen, France):
"beware of the pain that cedes to placebo: it's most certainly organic".
I have seen that proven again and again. I have no explanation other than the one given for the soldiers at anzio: The patient with "real" pain wants it to go away so much that any straw will be clutched at to relieve the pain, including placebo.
On the other hand, the patient with "psychological" pain gains from the pain in some manner. There will be much less incentive to see the pain relieved, and placebo may be as ineffective as the other pain medication.
As for the dose-response to placebo, the adverse reactions to placebos of high-dose NSAIDs are much more frequent that those to placebos of low- dose NSAIDs, in clinical trials. Go explain.
have a nice weekend
Nicholas Moore
Competing interests: None declared

Placebo Analgesia 25 October 2004

Peter KK Au-Yeung,
Specialist Anaesthetist
Hong Kong
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Re: Placebo Analgesia

A study published in the 1979 edition of Advances in Pain Research and Therapy offered a tantalizing glimpse of a possible mechanism for placebo analgesia.
A hundred or so patients who had wisdom teeth extraction were assigned (random doule blind) to a fixed dose of an opiate (morphine, I think) or the same volume of saline for post-operative analgesia. There was no statistically significant difference in the proportion of patients in the opiate versus the saline group who expressed satisfactory pain relief. Placebo analgesia worked in a case of organic pain, post-operative pain.
The researchers then broke the code after collecting analgesia data and then randomised (again double blind) the saline responders to saline or a dose of nalaxone. All the saline responders who got naloxone complained of their pain again. This suggests that endogenous analgesic systems involving enkephalins and/or endorphins might be involved.
So is placebo analgesia all in the mind? Or does the mind work via known neuropharmacological pathways?
Those interested in looking the paper up will have to make do with the following reference in non-standard manner: Fields HL and Basbaum AI in Advances in Pain Research and Therapy, Vol.3 Ed Bonica JJ et al. Raven Press, New York 1979 pp427-440
Competing interests: None declared

A biological mechanism for the placebo effect 26 October 2004

Dylan Evans,
Senior Lecturer
University of the West of England
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Re: A biological mechanism for the placebo effect

David Spiegel's comments on cin practice points to the need for more research into the underlying biological mechanisms that mediate the placebo effect. Such research cannot even begin, however, without novel hypotheses to test.
I have recently proposed that one pathway by which placebos might produce their effects is via the suppression of the acute phase response (inflammation and sickness behaviour). See:
Dylan Evans, Suppression of the acute-phase response as a biological mechanism for the placebo effect, Medical Hypotheses, In Press, Corrected Proof, Available online 6 October 2004, . (http://www.sciencedirect.com/science/article/B6WN2-4DGMR85- 6/2/64052c7a51cbf15cc8a6259b77c6ba35)
See also:
Dylan Evans. 2003 Placebo: The Belief Effect . London: Harper Collins. Republished by Harper Collins as Placebo: Mind over Matter in Modern Medicine in 2004.
---
Dylan Evans
Senior Lecturer in Intelligent Autonomous Systems
Faculty of Computing, Engineering and Mathematical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY
Web: www.dylan.org.uk
Competing interests: None declared

Using a Placebo may be unethical 27 October 2004

David Brookman,
senior lecturer
University of Newcastle (Australia)
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Re: Using a Placebo may be unethical

Excellent paper. For a placebo to be useful it is necessary for the practitioner to foster, or create belief in the efficacy of a treatment (s)he knows to be ineffective. This necessarily involves deception of the the patient and breaches the principle of patient autonomy. The utilitarian argument against this is that the patient is seeking relief from a psychological illness and cannot, or will not compehend the psychogenic nature of the illness, and the most benign method of intervention is to provide a placebo. Is our role as medical practitioners one to use science where science is capable of providing evidence of sufficent strength to support a decision, and satisfy clients wants and wishes when it is not? What is clearly inappropriate is for practitioners to foster interventions known to be ineffective simply to get rid of an irritating client, or because they are too lazy to seek evidence on what is effective.
Competing interests: None declared

Placebos in Practice and Research: Disentangling Medical Paradoxes 28 October 2004

Zelda Di Blasi,
Post-doctoral Fellow
University of California San Francisco, CA 94143 (USA),
David Reilly, Consultant Physician, Centre for Integrative Care, Glasgow Homeopathic Hospital, 1053 Great Western Road, Glasgow
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Re: Placebos in Practice and Research: Disentangling Medical Paradoxes

It is interesting to note that while it is unethical to prescribe placebos in clinical practice, dummy therapies are often an important ingredient of the �gold standard� research method in evidence-based- medicine. These are certainly ingenious ways to control for and separate the effects of specific therapies from non-specific factors such as hope and expectations. However, when a significant proportion of trial participants respond to placebos, this finding is perceived as a nuisance. Furthermore, when a significant proportion of participants respond to both the �active� therapy as well as the placebo, investigators often conclude that the treatment was ineffective. This �double-positive-paradox� (1) actually informs us that something quite powerful may be taking place.
Nitzan and Lichtenberg�s survey (2) highlights some of the limitations of conventional medicine in treating chronic and functional conditions and points to some of the current paradoxes in medicine. Placebos are described as �inert� and �inactive� interventions, yet placebo effects are �real� and �active� (3, 4). As pointed out in Spiegel�s editorial (5), hopes, feelings, and human relationships can influence the course of a physical illness and medical care. In a systematic review of placebo-controlled RCT�s we found some rigorous evidence to support this (6).
Doctors, at least in Israel, are giving placebos to patients without telling them, and investigators worldwide are often not telling their patients what treatment they got once their study is over (7). Similarly, an increasing proportion of patients are turning to alternative and complementary medicine, often without informing their primary physicians (8). What is this telling us about the level of trust and collaboration between patients and their providers? And how is this impacting the outcome of health care?
Little is known around the mechanisms and therapeutic effect of patient-practitioner interactions in medicine. A larger body of scientific knowledge can be found in the psychotherapy literature. In 1975, a review of 91 studies evaluating various psychotherapeutic interventions found that these were not different in terms of effectiveness, and concluded that �everybody has won and must have prizes� (9). In a recent textbook by the American Psychological Association, the therapeutic alliance was identified as the strongest predictor of outcome in psychotherapy (10).
Rather than continuing to evaluate the effectiveness of CAM therapies by adopting the biomedical approach and controlling for the potential confounders deriving from health care interactions, we should be examining the impact of these relationships and helping to restructure our health services around our findings.
We seem to have forgotten the extent to which each individual possesses natural self-healing capabilities and that these can be harnessed in a safe place with a care giver that is present, empathic and encouraging. Our health care system does not support this, impacting the quality of care we are able to provide (11,12).
For some, placebos may be a more gentle solution for functional symptoms or chronic conditions that conventional therapy is unable to treat, having less toxic properties than pharmacological therapies. However, secretly prescribing placebos can only increase the sense of mistrust between doctors and patients as well as the idea that physicians are not taking the patients� problem seriously.
The issue is not about whether we should prescribe placebos, but rather about the need to increase our general knowledge around healing and mind-body mechanisms (13), ways to understand and harness these in an ethical and practical manner, encouraging a sense of trust and partnership between the public and health care specialists.
Over thirty years ago McGuire described �three stages in the life of an artifact�: first it is ignored; then it is controlled for its presumed contaminating effects; and finally it is studied as an important phenomenon in its own right (14). It is time we stop considering perceptions, feelings and health care interactions as variables that need to be controlled in the pursuit of medical science, but include and study these as potentially meaningful mediators and moderators of therapeutic outcomes in clinical trials.
References
(1) Reilly D. Randomised controlled trials for homoeopathy. When is useful improvement a waste of time? Double positive paradox of negative trials. BMJ 2002;325:41;
(2) Nitzan U, Lichtenberg P. Questionnaire survey on use of placebo. BMJ 2004:329: 944-6.
(3) Leuchter, A. F., Cook, I. A., Witte, E. A., Morgan, M., & Abrams, M. Changes in brain function of depressed subjects during treatment with placebo. American Journal of Psychiatry 2002; 159 (1), 122- 129.
(4) Moseley, J. B., O'Malley, K., Petersen, N. J., Menke, T. J., Brody, B., Kuykendall, D. H., Hollingsworth, J. C., Ashton, C. M., & Wray, N. P. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. NEJM 2002; 2: 81-88.
(5) Spiegel, D. Placebos in practice. BMJ 2004;329:927-928
(6) Di Blasi, Z., Harkness, E., Ernst, E., Georgiou, A., & Kleijnen, J. Influence of context effects on health outcomes: a systematic review. The Lancet 2001; 357:757-62.
(7) Di Blasi Z, Kaptchuk TJ, Weinman J, & Kleijnen J. Informing participants of allocation to placebo at trial closure: a postal survey. BMJ 2002; 25:1329.
(8) Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998; 280:1569-75.
(9) Luborsky, L., Singer, B., & Luborsky, L. Comparative studies of psychotherapies: Is it true that "everyone has won and must have prices"? Archives of General Psychiatry, 1975. 32, 995-1005.
(10) Hubble, M. A., Duncan, B. L., & Miller, S. D. The Heart and Soul of Change: what works in therapy. 1999 (pp. 1-462). Washington D.C.: American Psychological Association.
(11) Mercer SW, Hasegawa H, Reilly D, Bikker AP. Length of consultations. Time and stress are limiting holistic care in Scotland. BMJ. 2002;325:1241.
(12) Freeman GK, Horder JP, Howie JG, Hungin AP, Hill AP, Shah NC, Wilson A. Evolving general practice consultation in Britain: issues of length and context. BMJ 2002; 324:880-2.
(13) Reilly D. Enhancing human healing. BMJ 2001;322:120-121.
(14) McGuire, W. J. (1969). Suspiciousness of experimenter's intent. In R. Rosenthal & R. L. Rosnow (Eds.), Artifact in behavioral research (pp. 13�57). New York: Academic Press.
Competing interests: None declared

Placebos in practice: conscious and unconscious use 31 October 2004

Magi Farre,
Clinical researcher.and Associate Professor Pharmacology
Pharmacology (Clinical Pharmacology). IMIM-UAB. Calle Doctor Aiguader, 80. 08003 Barcelona, Spain,
Yolanda Alvarez, Alexis Rodr�guez (HUVH), Sergio Abanades
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Re: Placebos in practice: conscious and unconscious use

We would like to extend some comments to the paper of David Spiegel about placebos in practice (issue 23 October). Use of placebo can also induce adverse effects (the named nocebo effect)(1). The prescription of placebo by doctors is commonly conscious, but also could be unconscious.
The conscious use of placebo in clinical practice has one important limitation, true placebos (inert substances) are usually not marketed and, as a consequence, can not be prescribed easily. To our knowledge, placebo is only present with its real name in some tablet packs of oral contraceptives. In Hospitals, inert placebo capsules can be prepared by pharmacist with non-active substances (e.g. lactose). As a consequence, doctors usually should prescribe active placebos (substances with pharmacological or therapeutic activity in other symptoms or diseases, but not in the present indication) (2,3,4). In our opinion the unconscious use of placebo by doctors is also frequent. In this case, doctors are not aware really that they are using placebo. This phenomenon can appear in the case of prescribing drugs when diagnosis is in doubt or is wrong, with the incorrect use of right medicines (lower dose, shorter duration), with the use of non-evidence based drugs or after the prescription of medicines in non-approved indications. In all these cases, prescribing drugs which have not proven beneficial effects may act only as a placebo but with the side-effects of the active drug (harmful placebo)(5,6). The apparent success of unconscious placebo treatment can mislead doctors into thinking that the diagnosis was correct and the treatment effective, but this may not be true. This phenomenon has been named �the therapeutic illusion�, that can reinforce the conduct of incorrect prescribing. Patients with therapeutic response to placebos can also present the therapeutic illusion (7).
1. Ferreres J, Ba�os JE, Farre M. El efecto nocebo: la otra cara del placebo [Nocebo effect: the other side of placebo]. Med Clin (Barc). 2004;122:511-6.
2. Grahame-Smith DG, Aronson JK. Placebos. In: Oxford Textbook of Clinical Pharmacology and Drug Therapy. Grahame-Smith DG, Aronson JK, editors. Oxford: Oxford University Press; 2002. p. 145-6.
3. Ba�os JE. Farre M. Efecto placebo. In: Principios de Farmacolog�a Cl�nica. Ba�os JE, Farre, editors. Barcelona: Masson 2002. p. 169-78.
4. Macedo A, Farre M, Ba�os JE. Placebo effect and placebos: what are we talking about? Some conceptual and historical considerations. Eur J Clin Pharmacol 2003;59:337-42.
5. Alvarez Y, Farre M. La �tica del placebo. FMC. 2001;8:201.
6. Laporte JR, Capella D. Useless drugs are not placebos. Lancet. 1987;1:1324.
7. Markus AC. The ethics of placebo prescribing. Mt Sinai J Med. 2000;67:140-3.
Competing interests: None declared

Undocumented editorial on placebos 5 November 2004

Peter C G�tzsche,
Director
Nordic Cochrane Centre, Copenhagen,
Asbj�rn Hr�bjartsson
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Re: Undocumented editorial on placebos

In his editorial on placebo (1), David Spiegel writes that our meta- analysis that compared placebo interventions with no treatment "had numerous problems", including lumping of heterogeneous trials. This all- embracing criticism is unwarranted.
We have previously responded to Spiegel�s comments (2) and explained that a broad approach to meta-analysis is often appropriate (3), in particular when there is no good a priori reason to exclude some conditions from consideration. And we also analysed disease conditions separately, if they had been investigated in at least three independent trials. The recently updated review now includes 182 trials, with binary outcome data for 4284 patients, and continuous outcome data for 7453 patients (4).
Thus, the relatively small loss of power by our preference for the clinically more relevant binary outcomes cannot explain why our results were largely negative.
It is correct that we reported a possible modest effect of placebo on pain, but Spiegel fails to mention that we also reported that the effect decreased significantly with increasing sample size, indicating possible bias (5). In addition, as studies comparing a placebo intervention with an untreated control group cannot be blinded, positive results were likely influenced by reporting bias. Thus, Spiegel�s optimistic interpretation is not tenable.
In the subtitle Spiegel claims that placebos �work in some conditions�. Instead of this opinion it would have been more instructive if he had clarified which conditions he refers to (besides pain), and presented systematically reviewed evidence for clinically important effects of placebo.
Peter C G�tzsche, director
pcg@cochrane.dk
Asbj�rn Hr�bjartsson, senior researcher
Nordic Cochrane Centre, H:S Rigshospitalet, Blegdamsvej 9, 2100 K�benhavn �, Denmark
1. Spiegel D. Placebos in practice. BMJ 2004;329:927-8.
2. Hr�bjartsson A, G�tzsche PC. Is the placebo powerless? N Engl J Med 2001;345:1278-9.
3. G�tzsche PC. Why we need a broad perspective on meta-analysis: It may be crucially important for patients. BMJ 2000;321:585-6.
4. Hr�bjartsson A, G�tzsche PC. Placebo interventions for all clinical conditions. The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003974.pub2.
5. Hr�bjartsson A, G�tzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344:1594-602.
Competing interests: None declared

Homeopathy? 5 November 2004

Alfred P J Lake,
Consultant in Anaesthesia and Pain Management
Glan Clwyd Hospital, LL18 5UJ.
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Re: Homeopathy?

The placebo effect is undoubtedly real and it is right to use it but both patients and their healthcare providers must acknowledge this and their employment of it.
Doubts may have been raised about the usefulness of the placebo response in conditions other than chronic pain but this, in fact, has very much in common with other chronic disease states where many interventions without good supportive evidence (and significant side effects) are daily advanced and it should, therefore, be of worth in them too.
Guidelines for placebo use are appropriate as we, indeed, cannot afford to dispense with any treatment that works even if we may not be certain how it does; what we must do, however, is to confirm efficacy. Considerable controversy may exist about the use of a biologically inert or irrelevant substance with therapeutic intent but isn�t such use, in fact, a daily occurrence? Doctors may not actively prescribe them but many patients make use of them particularly in the form of homeopathic remedies.
Homeopathic remedies are the best examples which, might I suggest, have not, in fact, been properly tested. I am not aware of a single study in which the homeopathic remedy itself has been tested as the only variable (though one could be set up without difficulty) and, in this age of evidence-based medicine and practice, I am concerned about the possible untested extension into the NHS mainstream as has been recently proposed by the Welsh Secretary for possible piloting in my region.
Competing interests: None declared

Re: Placebos in practice: conscious and unconscious use 6 November 2004

Peter KK Au-Yeung,
Staff Anaesthetist
Hong Kong
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Re: Re: Placebos in practice: conscious and unconscious use

Farre et al raised the question of off-label drug usage in their discussion about the use of placebos. I beg to differ that the use of a drug in a non-approved dose, frequency, duration, or even route necessarily constitutes unconscious use of placebos, in that it presupposes that the use of a drug in a non-approved manner must therefore be ineffective, or harmful.
Whilst I am not sufficiently familiar with the laws regulating medicines in various countries, I am given to believe that doctors do not necessarily get punished if they use drugs in a manner not fully compliant with licencing conditions. If there is sufficient clinical trial literature that a certain unapproved method of drug use is therapeutically advantageous, then the problem of negligence may not arise, even if such a way of using a drug has never and is not approved anywhere in the world.
One instance of this type of unapproved (by the regulatory bodies) but well established (by body of clinical trials) use of an anaesthetic drug is the epidural administration of fentanyl. Although the tide of opinion may well be turning against it now, it had enjoyed enormous popularity amopngst the anaesthetic communities all over the world. Surely this is not unconscious placebo usage.
It is perhaps salutary to note that in a discussion on off-label drug usage, it has been quoted that up to 30% of all prescriptions in General Medicine is off-label, ie fails to comply fully with licencing conditions.
Competing interests: None declared

Placebo is effective and it differs from sham drugs or "inadrugs" 17 November 2004

Markku Partinen,
MD, PhD, Chief neurologist
Rinnekoti Research Centre, FIN-02890 Espoo, Finland
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Re: Placebo is effective and it differs from sham drugs or "inadrugs"

Dear Sirs,
As it is written, placebo comes from Latin "I will please". Nocebo is the opposite to placebo. It is a pity that many physicians and especially the pharmacological field have adopted the term placebo to a sham drug used in comparative randomized clinical trials (RCT).
A RCT is never a perfect patient-physician relationship because the patient cannot be sure that her/his doctor is giving the best treatment. Also the Doctor's healing (placebo) effect differs from a situation, where the Doctor (or a therapist) is giving treatment that he/she trusts in. All medical personnel should always try to add their own therapeutic healing potential (the positive placebo effect) to the given pharmacological or surgical teatment. The effect of a postive placebo is often more than 25 or even more than 30 % of the total therapeutic effect of a drug. Why should we weaken the therapeutic by so much in neglecting the use of placebo in our routine daily work. In the same ways we should always avoid use of nocebo.
A good solution would be to use PLACEBO in its original meaning - pleasing the patient - trying to do the best to treat the patient. Some members in the alternative medicine field talk about energy healing. Placebo can be understod also as "energy healing" - whatever it means.
If the word placebo is used in its proper meaning a better word should be used in randomized clinical trials. We have such words, e.g a SHAM DRUG, or a SHAM TREATMENT. An alternaive is PHARMACOLOGICALLY INACTIVE DRUG. A new word could be invented. Could it be "INADRUG". I am sure that much better words could be found. Whatever a word is used, it should tell to us that we do not believe that this drug has any pharmacological activity. Placebo drug does really not equal calcium tablets that are used in clinical trials.
Competing interests: None declared