How could a placebo for a painkiller actually kill pain?

The 'drama' -- the seemingly magical disappearance of pain -- that occurred in the body of the surgeon-patient of the previous article on placebo, requires two separate 'dramatic' acts:

1) anticipation of relief, preceding
2) the experience of it.

Act 1: Anticipation or expectation of relief

The "stars" of Act 1 are the surgeon's prefrontal cortex (PFC), PFC_3.anim which orchestrates thoughts and actions in accordance with internal goals, and the Anterior Cingulate Cortex (ACC) ACC_1.animwhich is involved in processing emotion and motivation. [2][17][15][27]. The saline-induced relief from pain would not have occurred if there had not first been increased activity in these two locations due to the anticipation of relief from pain.

The surgeon's body was not responding to the essentially empty injection, so much as responding to his desperate-for-relief belief that the injection was morphine, a belief which begins with activity in the PreFrontal Cortex and the Anterior Cingulate Cortex.

How could the PFC do this?
How could the ACC do this?

Once the two locations 'decide' (in a very loose sense) that the injection is the real thing (i.e., morphine), they set into motion biochemical pathways The opiod system of endogenous ('self-made') opioids that activate painkilling pathways very similar to the pathways activated by the 'real' drug. That's why pain 'treatments' that are essentially just sugar or water can result in the lessening of pain. The placebo treatment looks identical enough to the 'active' treatment to create an expectation (assumption, anticipation) that it will have the same effect that the 'active' drug is reputed to have. The rest of the brain then responds to that expectation, triggering biochemical changes a the site of pain in the body, via nerves that lead from the brain through the spinal cord to the site.

Thus, most commercial drugs owe at least some degree of their success to a placebo response which is induced by belief in the drug[13]. To get an idea of which drugs have a placebo component and which don't, search 'clinical trial' thenameofthedrug 'placebo' and look for a statement which says something like "X percent responded to the drug, whereas only Y percent [usually a smaller percent] responded to placebo." If it says "0% responded to placebo", then the drug has no placebo component. Otherwise, the body's innate self-healing placebo response is at least part of that drug's ability to do what it does.

Not surprisingly, researchers have found as well that people who respond poorly to a placebo also tend to respond poorly to the 'active' treatment [15][17]. Thus, it's a misnomer to use the terms 'active treatment' versus 'placebo treatment': both treatments are 'active', and both are at least part 'placebo'.

responder to both placebo and active treatmentsResponder to placebo treatments
responder to both placebo and active treatmentsResponder to 'active' treatments
Responders to placebos and to traditional drugs appear to have the capability to summon up the biochemical pathways that underlie, at a minimum, the placebo response. Note: The existence of a placebo that works like a traditional treatment is not true for all diseases. The neural pathways involved in placebo have so far been studied extensively only for pain, depression, and Parkinson's disease. (Why not placebos for all diseases? )

But in terms of killing pain, responders to both active and placebo components of a treatment must, at a minimum, have functioning opioid pathways [15].
The opioid systemThe Opioid system

Act 2: the Experience of relief

Just as the PreFrontal Cortex and rostral Anterior Cingulate Cortex perform the act of anticipation/expectation , so do the pain-processing areas of the brain (the thalamus thalamus.anim.pingpong, the insula insula_1.anim and the caudal (rear) ACC caudal (rear) Anterior Cingulate Cortex ) take on, in the second act, the experience of pain relief. The biggest changes overall between anticipation of pain relief and the actual experience of it is that there is increased activity during anticipation in the structures responsible for the anticipation of relief, and decreased activity when pain lessens, in the structures responsible for the experience of relief.

(If the thalamus is insensitive to pain, why would it be involved? )

Figure 1 below shows the structures involved both in pain that is untreated (in the top half) as well as the structures affected by opioids (bottom left) and by placebos (bottom right).
Fig.1  from Petrovic et al. 2002(ref.15)Fig.1 from Petrovic et al. 2002(ref.15)
Expectation induced by a placebo for morphine (and for some other medicines) registers in the PreFrontal Cortex PFC_3d and has the end result of stimulating opioids which the body produces naturally (i.e., endogenous opioids) [20] [17]. Consider this: the chemical naloxone , when given as a injection, is known to block the painkilling effect of opioids, including morphine. What's amazing and yet entirely logical is that it also blocks the painkilling effect of a placebo, even in someone previously established as a placebo responder. [20] [15] [14] [22] [23] That's because morphine and a morphine-look-alike placebo (which stimlates endogenous opioids) engender very similar biochemical changes in response to pain -- changes that start in the brain and cascade from there. And thus both are blocked in similar ways by the same chemical (naloxone).

Indeed, and who would ever have 'thunk': An endogenous opioidlike material has been found in the cerebrospinal fluid of chronic pain patients whose pain level dropped following placebo administration [14].
Removing fluid from the spinal columnRemoving fluid from the spinal column
There is more detail about just how placebos activate the brain's descending pain control system in this Dec. 2009 Alternet article explaining new research published in Neuron and Science a couple months earlier . [33] [34]




2. Leuchter F et. al.: changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002; 122-129

13. Kirsch I, Sapirstein G: Listening to Prozac but hearing placebo : A meta-analysis of antidepressant medication. Prevention and Treatment 1998; 1(0002a)

14. Fields HL, Price DD: Toward a neurobiology of placebo analgesia, in The Placebo Effect: An Interdisciplinary Exploration. Edited by Harrington A. Cambridge, Mass., Harvard University Press, 1997 p.93-116

15. Petrovic P et. al.: Placebo and opioid analgesia – imaging a shared neuronal network. Science 2002; 295(5560): 1737-1740

17. Wager TD et. al.: Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 2004; 303(5661): 1162

20. Amanzio M, Benedetti F: Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated systems. Journal of Neuroscience 1997; 19(1): 484-494

22. Benedetti F et. al.: Somatotopic activation of opioid system s by target-directed expectations of analgesia. Journal of Neuroscience 1999; 19(9): 3639-3648

23. Johansen O, et. al.: Placebo and Nocebo Responses, cortisol, and circulating beta-endorphin. Psychosomatic Medicine 2003; 65: 786-790

27. de la Fuente-Fernandez et. al.: Placebo mechanisms and reward circuitry; clues from Parkinson's disease. Biological Psychiatry, 2004.

33. Falk Eippert Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia, Neuron, Volume 63, Issue 4, 27 August 2009, Pages 533-543, ISSN 0896-6273, DOI: 10.1016/j.neuron.2009.07.014. (

34. Falk Eippert et. al: Direct Evidence for Spinal Cord Involvement in Placebo Analgesia, Science 16 October 2009: Vol. 326. no. 5951, p. 404 (

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