The Parable About the Six Blind Men Touching Different Parts of the Elephant Describes

Seminowicz DA (2006 ) Believe in Your Placebo. J. Neurosci 26:4453-4454.

Kong J, Gollub RL, Rosman IS, Webb JM, Vangel MG, Kirsch I, Kaptchuk TJ (2006) Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging. J Neurosci 26:381–388.

Author’s response to “Believe in Your Placebo”

Seminowicz provides an insightful treatment of the current research of the role expectancy plays in the efficacy of placebo. We would add the following in an effort to continue and to cultivate the dialogue surrounding this important issue.

The current state of placebo research is much like the parable of six blind men touching different parts of an elephant and each believing that the part he touches describes the entire beast. A response to placebo treatment is a composite of discrete aspects of an entire phenomenon. One determinate of a placebo effect is the target symptom, such as pain or illness. Another is the type of treatment used as a placebo, which can be a number of inert treatment modalities such as placebo pills, sham device, or inert cream. A third determinate of placebo response is the set of beliefs held by the patient or subject about the efficacy of the treatment. One way to manipulate this latter component is by influencing the subjects’ expectation of how well the placebo will work. A fourth determinate is the metric used to evaluate the efficacy of the placebo. In the case of placebo analgesia, this would most likely be decreased rating of pain. Another determinate is whether the placebo treatment is performed in patients or healthy volunteers. Others include the patient-practitioner relationship; the practitioner him/herself and more that may not as yet be identified. As the study of placebo continues, it is important to consider how evaluating placebo from within different experimental paradigms will capture different facets of the phenomenon.

For example, although Pariente’sstudy and ours both investigated the same target symptom, pain, and both used sham acupuncture with the Streitberger Needle, using neuroimaging to investigate the neural basis of the placebo response; the two studies investigated different determinates of the placebo response.

In our study, we investigated the outcome metric of brain activity and subjective pain rating in response to calibrated experimental pain before and after sham acupuncture treatment. Our focus is the target symptom of pain relief.

In their study, Pariente and colleagues compared brain responses to three modes of stimulation: real acupuncture (RA), placebo acupuncture with Streitberger needle stimulation (SN), and overt placebo (OP, e.g. skin pricking) to directly assess the neural activity associated with the treatment. Their study is more closely related to previous fMRI / PET studies evaluating the brain response to acupuncture needle manipulation (Cho et al., 1998; Hui et al., 2000; Kong et al., 2002; Wu et al., 2002).

Rather than focus on pain rating changes as we did in our study, their study focused more on the brain activity associated with treatment type. Also, our study was performed in healthy subjects and Pariente et al studied subjects with chronic pain due to osteoarthritis. Pariente’s study did not find any outcome effects after any of the three treatments (the pain rating of pre-existing pain by osteoarthritis patients did not change). Also, Pariente’s study did NOT scan during the evocation of pain, only during the administration of the acupuncture/placebo treatment. In the brain imaging results, they found that RA produced greater activation than SN in insula ipsilateral to needling side although subjects thought both treatments were real. Both RA and SN evoked greater activation than OP (no treatment effect expected) in the right dorsolateral prefrontal cortex, anterior cingulate cortex, and midbrain.

As more studies add information to the body of knowledge about placebo effects, it is increasingly important to use caution when comparing or consolidating findings. Methodological differences may examine different attributes of the mechanisms underlying placebo effects and, as such, produce different results.

For instance, the inconsistent location of rostral anterior cingulate cortex (rACC) in different studies (Petrovic et al., 2002; Wager et al., 2004; deCharms et al., 2005; Pariente et al., 2005; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006) exemplifies this issue. These differences in reported location of activity in the rACC suggest that the different subdivisions of the rACC may have unique roles to play in the overall phenomenon of placebo analgesia.

Placebo analgesia is a very complicated phenomenon. Just as there are multiple determinates of the placebo phenomenon, so too it is likely that there are multiple neural circuits that may be activated during the evocation or expression of a placebo analgesia effect. Further, the activity in these different neural circuits may differ depending on circumstances (Colloca and Benedetti, 2005; Kong et al., 2006). As more information becomes clear about the nature of the placebo beast, it will be easier to integrate the information and to develop a clearer understanding of the whole. Neuroimaging has potential to contribute key information regarding each of these features of placebo.

Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C (2006) Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain 120:8-15.

Cho ZH, Chung SC, Jones JP, Park JB, Park HJ, Lee HJ, Wong EK, Min BI (1998) New findings of the correlation between acupoints and corresponding brain cortices using functional MRI. Proc Natl Acad Sci U S A 95:2670-2673.

Colloca L, Benedetti F (2005) Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 6:545-552.

deCharms RC, Maeda F, Glover GH, Ludlow D, Pauly JM, Soneji D, Gabrieli JD, Mackey SC (2005) Control over brain activation and pain learned by using real-time functional MRI. Proc Natl Acad Sci U S A 102:18626-18631.

Hui KK, Liu J, Makris N, Gollub RL, Chen AJ, Moore CI, Kennedy DN, Rosen BR, Kwong KK (2000) Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects. Hum Brain Mapp 9:13-25.

Kong J, Gollub RL, Rosman IS, Webb JM, Vangel MG, Kirsch I, Kaptchuk TJ (2006) Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging. J Neurosci 26:381-388.

Kong J, Ma L, Gollub RL, Wei J, Yang X, Li D, Weng X, Jia F, Wang C, Li F, Li R, Zhuang D (2002) A pilot study of functional magnetic resonance imaging of the brain during manual and electroacupuncture stimulation of acupuncture point (LI-4 Hegu) in normal subjects reveals differential brain activation between methods. J Altern Complement Med 8:411-419.

Pariente J, White P, Frackowiak RS, Lewith G (2005) Expectancy and belief modulate the neuronal substrates of pain treated by acupuncture. Neuroimage 25:1161-1167.

Petrovic P, Kalso E, Petersson KM, Ingvar M (2002) Placebo and opioid analgesia-- imaging a shared neuronal network. Science 295:1737-1740.

Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD (2004) Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303:1162-1167.

Wu MT, Sheen JM, Chuang KH, Yang P, Chin SL, Tsai CY, Chen CJ, Liao JR, Lai PH, Chu KA, Pan HB, Yang CF (2002) Neuronal specificity of acupuncture response: a fMRI study with electroacupuncture. Neuroimage 16:1028-1037.

Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS (2005) Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 25:7754-7762.