Creative consulting: more about placebos?

In the fifth article in his series David Reilly is joined by Zelda Di Blasi to look at the placebo response

If placebos are inactive, what is it that produces the remarkable changes? Do not ask what the placebo can do but, "What can the thing that responds to the placebo do?" You will end up thinking about self healing and self destructive processes.

Just as you can work backwards from a successful recovery to study healing reactions,¹ you can consider what placebo reactions say about healing responses and better care. If placebo can provoke a change indirectly perhaps we can learn to do so directly, because we are the only possible pathway for placebo action. The implications of this pathway, between our consciousness and our biology, can be missing in academic debate about placebo,^{2 3 4} but the discovery that people responding to placebo show definite brain scan changes can bring it back into focus.⁵

What can the placebo effect do?

Distress can be modified--as, for example, physical pain: in one study saline was as effective as morphine in 40% of people after surgery.⁶ The same goes for emotional pain: about 70% of patients respond to placebo for depression.⁷ So is the placebo effect all just in the mind? Does it only modify experience, not "objective" reality? When we blush when embarrassed is it "real"? It is as real as the quantitative electroencephalograph brain scans showing reduced prefrontal cortex activity in people responding to placebo antidepressants.⁵

How many respond?

It is often misquoted that one in three people are placebo responders. This is based on Beecher's original work analysing 1082 cases where "35.2% responded." The range, however, was 18-52%.⁸. Reported rates vary from less than 10% to more than 70% according to circumstances and context. Everyone has self healing potential.

Who responds?

There is probably no simple predictive measure of whether someone will or will not respond. People who respond to placebo have normal personalities, and those who do not have more rigid personalities, are suspicious, and sometimes do not respond to "ordinary medicine."⁹ Maybe it is only the gullible who respond: medical students respond more than most. In a study on the effects of psychotropics, of 300 medical students 50% had psychological changes and 60% had physical effects. They identified the pink pills as stimulants and the blue pills as sedatives. They were all placebos.¹⁰

What form?

The physical form of the intervention has an impact. Larger placebo capsules are viewed as stronger, and two are stronger than one. Injections produce larger effects than pills. Red capsules and yellow capsules tend to act as stimulants or antidepressants, blue capsules as sedatives, and white capsules as analgesics or narcotics.^{11 12 13}

Symbolism has impact, and none more so than the ritual of surgery.¹³ Surgeons made skin incisions in patients expecting to have their internal mammary artery tied to help blood flow to their heart, to help with their angina. A random selection of patients, however, never had the operation and the incision was sewn back up. All 18 non-treated patients had less angina six weeks afterwards, some had improved exercise electrocardiographs, and the effect lasted for years in some.¹⁴

In which culture?

The advertisements, the packaging, and the hypnotic names carry messages--for example, "Welldorm" for insomnia and "Marvelon" as a marvellous contraceptive.¹⁵ The brand name on that free plastic pen the drug representative gives to us has an effect. In one study, branded tablets were significantly more effective than unbranded tablets for the treatment of headaches.¹⁶ A powerful message in one culture may be meaningless in another.

Expecting what?

You tend to get what you expect. From aspirin placebo you get aspirin-like effects; from morphine you get morphine-like effects and side effects. This system has puzzling specificity, and placebos interact with drug action synergistically or disruptively. Bronchoconstriction due to atropine and other anticholinergics can be reversed by suggestion (with saline inhalation) and bronchoconstriction of suggestion can be blocked by ipratropium.¹⁷ Your previous experience and learning all have an effect like Pavlov's dogs salivating to the sound of the feeding bell. Rats given repeated scopolamine injections show the same depressed behaviour when given later placebo injections.¹⁸ If a prescription helped (say in reducing your anxiety), you might repeat what you "learned" to a later placebo version of the same treatment. So it is better to "anchor" the patient on their own self coping than on you or your treatments.

Drugs are modelled in the laboratory and tested in animals. It is naive, however, to expect only predictable "hard" pharmacological outcomes. They become an ingredient in a complex reactive system. This means it is also naive to believe that the real effect is that part left over after subtracting the placebo: one plus one might come out as four, and you might be one of the active ingredients.

From which carer?

Push the square peg of medicine into the round hole of healing and you end up with ugly words, like iatroplacebogenics, to explain that results are influenced by who does the caring and how.¹⁹ The carer's personality and attitude, their warmth, empathy or hostility towards the patient, and their attitude towards the treatment (active enthusiastic or passive nihilistic) all affect outcome. A review of controlled trials found that doctors who adopted a warm, friendly, and reassuring manner were more effective than those whose consultations were formal and did not offer reassurance.²⁰ Good caring and a weak medicine can give a better outcome than poor caring and a strong medicine.²¹ This means that the placebo arm of one study can sometimes have better results than the "active" arm of another. This causes endless confusion and complicates the search for evidence based practice.

Single blinded design is even less reliable, which brings us back to expectations. In a study of people having teeth removed, patients were told that they might get one of three injections for pain control that would make their pain better (fentanyl, a strong pain killer), worse (naloxone, an opiate antagonist that would make pain worse), or have no effect (placebo). The patient was "blind" but the dentist knew which group each patient was in.²²

Response of patients when dentists knew they would get an injection with no chance of pain relief (PN, placebo or naloxone) or a 1 in 3 chance of pain relief (PNF, placebo, naloxone, or fentanyl ²²) (reprinted with permission from Elsevier Science (The Lancet 1985; i: 43))

The graph shows the response to placebo in the two groups. When the dentists knew the patient had a chance of a "real" painkiller, the placebo was "activated" and was as distinct from the other placebo response as a "real" medicine from a dummy medicine. The carer knew there was a chance of receiving a "real" medicine and somehow transmitted this to patients, who then activated their own healing systems.

We can just as readily destroy such a reaction. Patients receiving eight weeks of placebo or antidepressants were improving equally until those taking placebo were told so.⁵ Most deteriorated and ended up taking medications.²³

Conclusion

So the treatment, its presentation, and its expected effects interact with patient factors blended with the carer and the context to affect healing systems. It seems that the best results are achieved when a patient has confidence in the carer, the institution, or the system of care, and when these are congruent with the patient's attitudes, beliefs, and expectations. Western medicine has often ignored or marginalised direct engagement with self healing (hypnotherapy is an important exception), but, as the box shows, anthropologists have seen that every human culture expresses these same dimensions, consciously or not.

David Reilly, consultant physician, Homeopathic Hospital, Glasgow
Email: davidreilly1@compuserve.com


studentBMJ 2002;10:45-88 March ISSN 0966-6494

1. Reilly D. Creative consulting: what modifies a healing response? studentBMJ 2002;10:12-3. (January.)
2. Kienle GS, Kiene H. The powerful placebo effect: fact or fiction ? J Clin Epidemiol 1997;50:1311-8.
3. Kienle GS, Kiene H. The placebo effect: a scientific critique. Complement Ther Med 1998;6:14-24.
4. 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.
5. Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002;159:122-9.
6. Beecher HK. Increased stress and effectiveness of placebos and "active" drugs. Science 1960;132:91-2.
7. Kirsch I, Sapirstein G. Listening to Prozac but hearing placebo: a meta-analysis or antidepressant medication. In: Kirsch I, ed. Expectancy, experience and behaviour. Washington, DC: American Psychological Association, 1999.
8. Beecher HK. The powerful placebo. JAMA 1955;159:1602-6.
9. Lasagna L, Mosteller F, von Felsinger JM, Beecher HK. A study of the placebo response. Am J Med 1954;16:770-9.
10. Blackwell B, Bloomfield SS, Buncher CR. Demonstration to medical students of placebo responses and non-drug factors. Lancet 1972;13i:1-11.
11. Buckalew LW, Coffield KE. An investigation of drug expectancy as a function of capsule colour and size and preparation form. J Clin Psychopharmacol 1982;2:245-8.
12. De Craen AJM, Roos PJ, de Vries AL, Kleijnen J. Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness. BMJ 1996;313:1624-6.
13. Beecher HK. Surgery as placebo. JAMA 1961;176:1102-7.
14. Cobb L, Thomas GI, Dillard DH, Merendino KA, Bruce RA. An evaluation of internal-mammary-artery ligation by a double-blind technique. N Engl J Med 1959;260:1115-8.
15. Holm S, Evans M. Product names, proper claims? More ethical issues in the marketing of drugs. BMJ 1996;313:1627-9.
16. Branthwaite A, Cooper P. Analgesic effects of branding in treatment of headaches. BMJ 1981;282:1576-8.
17. Butler C, Steptoe A. Placebo responses: an experimental study of psychophysiological processes in asthmatic volunteers. Br J Clin Psychol 1986;25:173-83.
18. Herrnstein RJ. Placebo effect in the rat. Science 1962;138:677-8.
19. Shapiro AK. Iatroplacebogenics. Int J Pharmacopsychiat. 1969;2:215.
20. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of context effects on health outcomes: a systematic review. Lancet 2001;357:757-62.
21. Walach H. The efficacy paradox in randomised controlled trials of CAM and elsewhere: beware of the placebo trap. J Altern Complement Med 2001;7:213-8.
22. Gracely RH, Dubner R, Deeter WR, Wolksee PJ. Clinicians' expectations influence placebo analgesia. Lancet 1985;i:4.
23. Fox, M. Brain scan study shows how placebo aids depression. Washington: Reuters, 2002. www.forbes.com/newswire/2002/01/01/rtr467478.html (accessed 5 Feb 2002).
24. Helman H. Placebo and nocebos: the cultural construction of belief. In: Peters D, ed. The placebo response: biology and belief. London: Churchill Livingstone, 2001.