NIH Public Access

Author Manuscript
Pain. Author manuscript; available in PMC 2013 April 15.
Published in final edited form as:
NIH-PA Author Manuscript

Pain. 2013 April ; 154(4): 511–514. doi:10.1016/j.pain.2013.02.002.

Placebo analgesia: Psychological and neurobiological

mechanisms
Luana Colloca1, Regine Klinger2, Herta Flor3, and Ulrike Bingel4
1National Center for Complementary and Alternative Medicine (NCCAM), National Institute of

Mental Health (NIMH) and Clinical Center, Department of Bioethics, National Institutes of Health
(NIH), Bethesda, USA
2Outpatient
Clinic of Behavior Therapy, Department of Psychology, University of Hamburg,
Hamburg, Germany
3Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical
Faculty Mannheim, Heidelberg University, Mannheim, Germany
4NeuroImage Nord, Department of Neurology, University Medical Center Hamburg-Eppendorf,
NIH-PA Author Manuscript

Hamburg, Germany

Introduction
Placebos and placebo effects have held an ambivalent place in health care for at least two
centuries. On the one hand, placebos are traditionally used as controls in clinical trials to
correct for biases. Among other factors, these include regression to the mean, the natural
course of the disorder, and effective co-interventions. In this context, the placebo effect is
viewed as an effect to be factored out in order to isolate and accurately measure the specific
effects of the treatment. On the other hand, there is mounting scientific evidence that
placebo responses represent complex psychoneurobiological events involving the
contribution of distinct central nervous system as well as peripheral physiological
mechanisms that influence pain perception, clinical symptoms, and substantially modulate
the response to active analgesics.

In this review, we bring together three perspectives of placebo research including

psychological mechanisms, neurobiological pathways and molecular substrates of placebo
NIH-PA Author Manuscript

analgesia and their contribution to active pain medications. The emphasis is particularly on
recent studies illuminating mechanisms underlying individual differences in placebo
responsiveness.

Psychological aspects of placebo analgesia

From a psychological point of view, a series of recent studies supported the nature of the
placebo effect as a learning phenomenon wherein a human being learns to produce a benefit
via verbally-induced expectations, cued and contextual conditioning or social learning [9;
11]. Placebo analgesic effects can be elicited by verbal instructions that anticipate a benefit,
thus creating expectations of analgesia and recalling previously acquired experiences of pain

Correspondence to: Luana Colloca, MD, PhD -- Building 10, Room 1C154, Bethesda, MD 20892-1156; Phone: (301) 435-8715; Fax:
(301) 496-0760; luana.colloca@nih.gov.
Conflict of interests: The authors have not conflicts of interest to declare.
Disclosure: The opinions expressed by LC are those of the author and do not necessarily reflect the position or policy of the National
Institutes of Health, the Public Health Service, or the Department of Health and Human Services.
 Colloca et al. Page 2

relief. These verbally-induced expectations can be reinforced through manipulations in

which a placebo treatment is paired with reduced pain intensities so that subjects come to
experience analgesia and thereby enhance their expectations of future pain relief [28; 8; 11].
NIH-PA Author Manuscript

This procedure typically evokes much stronger and more stable placebo analgesic effects
compared to verbally-induced effects [8; 16]. Interestingly, recent evidence suggests that
these effects can be triggered by contextual cues that are not consciously perceived
suggesting that placebo analgesic responses can operate outside of conscious awareness
[15]. It is also noteworthy that conditioning can be induced by repetitive exposure to
pharmacological treatments and produces drug-like effects when the active drug is replaced
by a placebo. These effects, termed pharmacological conditioning, are quite robust in the
field of pain and other conditions. Intriguingly, placebos given after preexposure to
pharmacological treatments mirror the action of the pharmacological agent such as
analgesics, for example, morphine and ketorolac [1], the immunosuppressant cyclosporin A
[21], the dopamine-agonist apomorphine [5], the benzodiazepine receptor agonist midazolan
and antagonist flumazenil [23], supporting the fact that placebos induce physiologically
specific effects via learning processes.

Placebo analgesic effects can also occur without formal conditioning and direct prior
experience because crucial information necessary to build up expectations of analgesia can
be acquired through social learning. Colloca and Benedetti showed that substantial placebo
analgesic responses were present after observing a benefit in another person undergoing an
NIH-PA Author Manuscript

analgesic treatment [9]. Remarkably, the placebo analgesic effects following the observation
of a benefit in another person were similar in magnitude to those induced by directly
experiencing the benefit through a conditioning procedure and were positively correlated
with the individual empathy traits of the observer. These observations emphasize that
contextual cues and the entire atmosphere surrounding the participant or patient contribute
to induce expectations of clinical benefit and recall memories of pain relief and thereby
substantially modulate the individual placebo analgesic response.

Neurochemistry of placebo analgesia

The above-described mechanisms are associated with specific central nervous system and
peripheral physiological responses. Beginning with experiments in the 1960s, evidence from
indirect pharmacological approaches and molecular imaging studies with positron emission
tomography (PET) indicated that placebo analgesia is mediated by the release of
endogenous neuromodulators, including opioids, cholecystokinin, cannabinoids and
dopamine. Levine, Gordon and Fields [18] first demonstrated that placebo analgesia can be
antagonized by naloxone, suggesting the involvement of endogenous release of opioids.
Since then, the contribution of opioidergic neurotransmission in placebo analgesia has been
NIH-PA Author Manuscript

corroborated by behavioral and functional magnetic resonance imaging (fMRI) studies using
the opioid antagonist naloxone and PET studies using in vivo receptor binding approaches
with opioidergic ligands [1; 33; 32; 11]. The changes in opioidergic neurotransmission are
associated with the modulation of the dopaminergic system suggesting that both endogenous
opioids and dopamine contribute to the individual placebo analgesic response [26].
However, the distinct role of the dopaminergic system in placebo analgesia needs to be
further investigated.

Recently, placebo analgesia has also been linked to the cannabinoid system [3]. This system
seems to underlie placebo analgesia after pharmacological conditioning with the non-
steroidal anti-inflammatory drug (NSAID) ketorolac In this case, placebo analgesic
responses were reversed by the CB1 receptor antagonist rimonabant, indicating that the
effects elicited by NSAID conditioning are partially mediated by the endogenous release of

Pain. Author manuscript; available in PMC 2013 April 15.

 Colloca et al. Page 3

cannabinoids [3]. Importantly, placebo analgesia can be negatively modulated by the release
of cholecystokinin as indicated by the antagonist action of proglumide [4].
NIH-PA Author Manuscript

Overall, these findings support the notion that the neurobiological effects of placebo
analgesia are related to neuromodulators that are released in our brain under different
contexts. Further research needs to clarify the interactions between the different systems
involved in placebo analgesia under physiological and pathological conditions (e.g., acute
and chronic pain). It is important to understand where in the brain these changes take place
and what the mechanisms initiating and mediating these changes in neurochemistry are.

Neurophysiology of placebo analgesia

Functional neuroimaging studies indicate that placebo analgesia involves a top-down
activation of endogenous analgesic activity via the descending pain modulatory system.
Specifically, placebo analgesia has been shown to be associated with activity changes and
enhanced functional coupling of the dorsolateral prefrontal cortex (DLPFC), the anterior
cingulate cortex (ACC) and distinct subcortical structures such as the hypothalamus,
amygdalae and the periaqueductal grey (PAG) [31; 6; 11; 19]. Within this network of brain
regions the DLPFC seems to be crucially involved in the initiation of the placebo analgesic
response, whereas rACC to PAG connectivity has been shown to correlate with the
reduction of pain-related responses in somatosensory pain areas and the behavioral changes
NIH-PA Author Manuscript

in pain reports [31; 6; 11; 19].

Moreover, neuroimaging studies indicate that the reduced pain ratings during placebo
analgesia are paralleled by decreased activity in the classical pain processing areas including
the thalamus, insula and the somatosensory cortex [24; 31; 6; 25; 11; 20; 30]. Evidence from
spinal cord fMRI further revealed that pain-related activity in the ipsilateral dorsal horn,
corresponding to painful stimulation, is substantially reduced under placebo [12] and
thereby provides evidence for spinal inhibition during placebo analgesia. Together these
studies support the notion that altered pain experience during placebo analgesia, at least in
part, results from active inhibition of nociceptive activity as depicted in Figure 1.

However, other neuroimaging studies on placebo analgesia involving novel methodological

approaches including multivariate pattern analyses and meta-analyses of brain imaging
studies, support the relevance of changes in intracortical, emotion-related circuitry to induce
and predict placebo analgesia [29]. Future studies have to unravel the distinct contribution
and potential interaction of these mechanisms.

Relation between the pharmacodynamics of a drug and the placebo

NIH-PA Author Manuscript

component
Placebo effects are inherent to every treatment and significantly contribute to clinical
outcome even in the presence of strong analgesic treatments such as the opioid agonist
morphine in post-operative patients or remifentanil in healthy subjects [10; 7]. This is best
illustrated in the so-called open/hidden drug paradigm [2]. In this paradigm, identical
concentrations of the same analgesic are administrated under two conditions: an open
condition, in which the patient is aware of the time-point at which the medication is
administrated by a health practitioner and a hidden condition in which the patient is unaware
of the medication being delivered by a preprogrammed infusion machine. The comparison
of both conditions allows for the dissociation of the genuine pharmacodynamic effect of the
treatment (hidden treatment) and the additional analgesic benefit of the psychosocial context
in which the treatment is provided. By using this paradigm, post-surgery patients who
received their analgesic treatments in presence of a physician required a much lower dose of

Pain. Author manuscript; available in PMC 2013 April 15.

 Colloca et al. Page 4

morphine to reduce their pain by 50% than those who received the medication from a
preprogrammed infusion machine [10]. These studies provide compelling evidence that the
simple awareness of a being treated considerably enhances the overall analgesic effect in
NIH-PA Author Manuscript

both experimental and clinical settings. These findings have recently been corroborated by
brain imaging approaches. Remifentanil administrated overtly as compared to an
administration given covertly, enhanced substantially the analgesic changes in the neural
activity of brain regions involved with the coding of pain intensity [7]. One of the crucial yet
unanswered questions is whether placebo responses and pharmacologically-induced
analgesia combine in an additive or interactive manner. Clinically speaking,
pharmacologically-induced analgesia and the distinct endogenous cascades triggered by
placebo mechanisms may combine in additive or interactive manner depending on the given
analgesic treatment (i.e. opioidergic or non-opioidergic analgesics). Future studies involving
different methodologies and designs should aim at unraveling how placebo responses and
pharmacological analgesia combine or interact at a receptor/molecular level.

Interindividual differences and predictability of placebo analgesic

responses
In both experimental and clinical conditions, the placebo response varies tremendously
among individuals. The individual placebo analgesic response can range from no effect
(‘non-responders’) to complete pain relief. Much effort is currently being dedicated to the
NIH-PA Author Manuscript

identification of psychosocial and biological markers that moderate individual proneness to

form placebo responses. Available evidence supports the putative relevance of several
psychosocial variables for placebo responsiveness. Many studies have explored different
psychological traits as potential predictors of placebo responses. These include, among
others, trait and state anxiety, dispositional optimism, hypnotic suggestibility, coping
abilities and the locus of control. Many of these studies however, included small sample
sizes what might contribute to the often conflicting results.

Only recently the ability to trigger the cascade of endogenous opioids has been directly
linked to psychological traits. Higher levels of endogenous opioids in a placebo paradigm
have been observed in those subjects who scored high on personality traits such as
agreeableness and resilience, qualities that allow people to have an optimistic view of
human nature and cope with stress and adversity [22].

Another factor that may partially account for an individual’s placebo analgesic
responsiveness is the variation in genetic variables. This has recently been documented in
patients with irritable bowel syndrome (IBS) [13]. These chronic pain patients were assigned
to one of three treatment arms: no-treatment (‘waitlist’), placebo treatment with a ‘limited’
NIH-PA Author Manuscript

patient-health practitioner interaction and placebo treatment with an ‘augmented’ supportive

patient-health practitioner interaction. The primary outcome, change from baseline in IBS-
Symptom Severity Scale after three weeks of treatment, was correlated with the number of
methionine alleles in the COMT val158met polymorphism (rs4633). Patients who were met/
met homozygotes showed the strongest placebo analgesic effect under the augmented
placebo arm whilst patients who were val/val homozygotes were less responsive to warm
and caring physicians and thus minimally benefiting from placebo responses [13].

Latest evidence supports the notion that also an individual’s brain anatomy including
structural and functional measures predicts the capacity for placebo analgesic responses in
healthy subjects. Stein et al. [27] indicated that white matter integrity in dorsolateral
prefrontal cortex and rostral anterior cingulate cortex and their pathways to the
periaqueductal grey are positively associated with individual placebo analgesic responses in
healthy subjects. This finding supports the importance of structural brain connectivity in

Pain. Author manuscript; available in PMC 2013 April 15.

 Colloca et al. Page 5

determining the individual ability to form placebo analgesic responses. Along these lines,
resting state functional connectivity between prefrontal and insular/parietal cortices has also
been shown to predict individual placebo analgesic responses in patients suffering from
NIH-PA Author Manuscript

chronic low back pain [14], and expectancy-related modulation of pain in healthy volunteers
[17].

Given that placebo analgesic responses fundamentally contribute to the overall analgesic
outcome, a more detailed knowledge about the individual markers of placebo responsiveness
may help to personalize therapeutic protocols and optimize patient-clinician interactions as
well as patient stratification in clinical trials.

Concluding remarks
In summary, the available scientific evidence indicates that placebo analgesic responses are
mediated by psychoneurobiological mechanisms and molecular targets and that these effects
substantially contribute to the overall effectiveness of analgesic treatments. Recent advances
in the field have paved the way for how neuropsychological, genetic and brain-related
variables may predict individual differences in placebo responsiveness. Further insights into
the mechanisms of placebo analgesia, its modulation of analgesic drug pharmacodynamics,
and importantly, its predictability is urgently needed to guide future translational research
and improve the methodology of clinical trials and clinical practice (see Part 2 of this review
NIH-PA Author Manuscript

on clinical applications).

Acknowledgments
This research was funded by intramural NCCAM and NIMH (L.C.); grants by the Deutsche
Forschungsgemeinschaft (FOR 1328/1), (Kl 1350/3-1) (R.K.), (Fl 156/33-1) (H.F.) and (BI 789/2-1) (U.B.); and
grants by the Bundesministerium für Bildung und Forschung (01GQ0808) (U.B.).

References
1. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-
activated opioid systems versus conditioning-activated specific subsystems. J Neurosci. 1999;
19(1):484–494. [PubMed: 9870976]
2. Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: a role for non-
specific activation of endogenous opioids. Pain. 2001; 90(3):205–215. [PubMed: 11207392]
3. Benedetti F, Amanzio M, Rosato R, Blanchard C. Nonopioid placebo analgesia is mediated by CB1
cannabinoid receptors. Nat Med. 2011; 17(10):1228–1230. [PubMed: 21963514]
4. Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of
the hyperalgesic nocebo effect. J Neurosci. 2006; 26(46):12014–12022. [PubMed: 17108175]
NIH-PA Author Manuscript

5. Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, Bergamasco B, Lopiano L.

Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic
nucleus. Nat Neurosci. 2004; 7(6):587–588. [PubMed: 15146189]
6. Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C. Mechanisms of placebo analgesia: rACC
recruitment of a subcortical antinociceptive network. Pain. 2006; 120(1–2):8–15. [PubMed:
16364549]
7. Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, Tracey I. The
effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid
remifentanil. Sci Transl Med. 2011; 3(70):70ra14.
8. Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain. 2006; 124(1–2):126–
133. [PubMed: 16701952]
9. Colloca L, Benedetti F. Placebo analgesia induced by social observational learning. Pain. 2009;
144(1–2):28–34. [PubMed: 19278785]

Pain. Author manuscript; available in PMC 2013 April 15.

 Colloca et al. Page 6

10. Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt versus covert treatment for pain, anxiety, and
Parkinson’s disease. Lancet Neurol. 2004; 3(11):679–684. [PubMed: 15488461]
11. Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, Buchel C. Activation of the
NIH-PA Author Manuscript

opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009; 63(4):533–
543. [PubMed: 19709634]
12. Eippert F, Finsterbusch J, Bingel U, Buchel C. Direct evidence for spinal cord involvement in
placebo analgesia. Science. 2009; 326(5951):404. [PubMed: 19833962]
13. Hall KT, Lembo AJ, Kirsch I, Ziogas DC, Douaiher J, Jensen KB, Conboy LA, Kelley JM,
Kokkotou E, Kaptchuk TJ. Catechol-O-Methyltransferase val158met Polymorphism Predicts
Placebo Effect in Irritable Bowel Syndrome. PLoS One. 2012; 7(10):e48135. [PubMed:
23110189]
14. Hashmi JA, Baria AT, Baliki MN, Huang L, Schnitzer TJ, Apkarian AV. Brain networks
predicting placebo analgesia in a clinical trialfor chronic back pain. Pain. 2012; 153(12):2393–
2402. [PubMed: 22985900]
15. Jensen KB, Kaptchuk TJ, Kirsch I, Raicek J, Lindstrom KM, Berna C, Gollub RL, Ingvar M, Kong
J. Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci U S A.
2012; 109(39):15959–15964. [PubMed: 23019380]
16. Klinger R, Soost S, Flor H, Worm M. Classical conditioning and expectancy in placebo
hypoalgesia: a randomized controlled study in patients with atopic dermatitis and persons with
healthy skin. Pain. 2007; 128(1–2):31–39. [PubMed: 17030095]
17. Kong J, Jensen K, Loiotile R, Cheetham A, Wey H-Y, Tan Y, Rosen B, Smoller JW, Kaptchuk TJ,
NIH-PA Author Manuscript

Gollub RL. Functional connectivity of frontoparietal network predicts cognitive modulation of

pain. Pain. 2012 in press.
18. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet. 1978; 2(8091):
654–657. [PubMed: 80579]
19. Lui F, Colloca L, Duzzi D, Anchisi D, Benedetti F, Porro CA. Neural bases of conditioned placebo
analgesia. Pain. 2010; 151(3):816–824. [PubMed: 20943318]
20. Lyby PS, Aslaksen PM, Flaten MA. Variability in placebo analgesia and the role of fear of pain -
an ERP study. Pain. 2011; 152(10):2405–2412. [PubMed: 21875771]
21. Ober K, Benson S, Vogelsang M, Bylica A, Gunther D, Witzke O, Kribben A, Engler H,
Schedlowski M. Plasma noradrenaline and state anxiety levels predict placebo response in learned
immunosuppression. Clin Pharmacol Ther. 2012; 91(2):220–226. [PubMed: 22166852]
22. Pecina M, Azhar H, Love TM, Lu T, Fredrickson BL, Stohler CS, Zubieta JK. Personality Trait
Predictors of Placebo Analgesia and Neurobiological Correlates. Neuropsychopharmacology. 2012
23. Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M. Placebo in emotional
processing--induced expectations of anxiety relief activate a generalized modulatory network.
Neuron. 2005; 46(6):957–969. [PubMed: 15953423]
24. Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia-- imaging a shared
neuronal network. Science. 2002; 295(5560):1737–1740. [PubMed: 11834781]
NIH-PA Author Manuscript

25. Price DD, Craggs J, Verne GN, Perlstein WM, Robinson ME. Placebo analgesia is accompanied
by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain. 2007;
127(1–2):63–72. [PubMed: 16963184]
26. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Placebo and nocebo effects
are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry. 2008; 65(2):
220–231. [PubMed: 18250260]
27. Stein N, Sprenger C, Scholz J, Wiech K, Bingel U. White matter integrity of the descending pain
modulatory system is associated with interindividual differences in placebo analgesia. Pain. 2012;
153(11):2210–2217. [PubMed: 22959599]
28. Voudouris NJ, Peck CL, Coleman G. Conditioned placebo responses. J Pers Soc Psychol. 1985;
48(1):47–53. [PubMed: 3981392]
29. Wager TD, Atlas LY, Leotti LA, Rilling JK. Predicting individual differences in placebo analgesia:
contributions of brain activity during anticipation and pain experience. J Neurosci. 2011; 31(2):
439–452. [PubMed: 21228154]
30. Wager TD, Fields H. Placebo analgesia. Textbook of Pain. in press.

Pain. Author manuscript; available in PMC 2013 April 15.

 Colloca et al. Page 7

31. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM,
Cohen JD. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science.
2004; 303(5661):1162–1167. [PubMed: 14976306]
NIH-PA Author Manuscript

32. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain. Proc
Natl Acad Sci U S A. 2007; 104(26):11056–11061. [PubMed: 17578917]
33. Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS.
Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 2005;
25(34):7754–7762. [PubMed: 16120776]
NIH-PA Author Manuscript
NIH-PA Author Manuscript

Pain. Author manuscript; available in PMC 2013 April 15.

 Colloca et al. Page 8
NIH-PA Author Manuscript
NIH-PA Author Manuscript

Figure 1.
Psychological mechanisms such as verbally-induced expectations, cued and contextual
conditioning and social learning trigger the cascade of endogenous opioids and non-opioids.
The result is an alteration of the pain experience that at least in part, induces an active
inhibition of nociceptive activity and modulation of brain areas predicting placebo analgesic
responses.
PFC, prefrontal cortex; ACC, anterior cingulate cortex; SI, primary somatosensory cortex;
SII secondary somatosensory cortex; PAG, periacqueductal gray.
NIH-PA Author Manuscript

Pain. Author manuscript; available in PMC 2013 April 15.