Abstract

Introduction

The terms placebo and nocebo effects refer respectively to the positive and negative cognitive modulation of behaviors and outcomes [1••]. Placebo and nocebo effects in the arena of pain are triggered by verbal instructions, conditioning, social observation, and interactions [1••, 2•]. Verbal instructions suggesting pain relief can induce placebo analgesia by recalling a prior experience of analgesia and increasing the desire to get better. Placebo analgesia (and likewise expectations of pain relief) [3] can be enhanced by conditioning, in which a simulation of benefit (e.g. an analgesic cream paired with a decrease of the intensity of painful stimuli) evokes analgesia when a control level of pain is delivered. Typically, conditioned placebo effects induce stronger and longer-lasting (up to 4–7 days) effects [4] compared with verbal suggestions alone in pain [5–9] and tactile perception [10, 11]. A recent study investigated the role of awareness in conditioned placebo analgesic effects and found that visual cues that are unconsciously perceived elicit analgesic responses, suggesting that learning mechanisms trigger these effects by partially operating outside of awareness [12]. When conditioning paradigms involve repetitive exposure to pharmacologic treatments, the result is a drug-like effect associated to the administration of a placebo that acts as a dose-extender of the effect of drug inherent to the treatment under investigation [5, 13]. For example, a placebo given after a repetitive administration of nonopioid drugs such as aspirin or ketorolac produces an aspirin- or ketorolac-like effect, respectively, while a placebo given after the opioid drug morphine produces morphine-like effects such as reduction of pain and morphine-induced adverse events [14, 15••, 16, 17]. The fact that placebos given after pharmacologic conditioning trigger drug-like physiological effects has tremendous value at a theoretical level as well as potential for the clinical practice.

Placebo effects also occur without direct first-hand experience via social observations, which may facilitate the process of building up expectations of analgesia. Colloca and Benedetti demonstrated that placebo analgesia is observable in healthy patients who have observed a benefit in another person [18]. When tested for pain, the observers showed placebo analgesia and the magnitude of observationally-induced analgesia was comparable with that induced by a conditioning procedure, in which patients directly experienced the benefic effect. Notably, placebo analgesic effects were correlated with empathy scores, suggesting that the ability to empathize another’s feelings may facilitate these effects. However, the effect of empathy only seems to play a role when interpersonal interactions are involved [18, 19], since placebo effects following the observation of a video are not linked to the level of individual empathy [20]. Interestingly, behavioral nocebo effects are also modulated by observing another person in pain [21] suggesting that common brain mechanisms might account for these effects. Psychosocial cues and the entire set of interpersonal interactions contribute to induce expectations and potentially recall memories of analgesia. This phenomenon also occurs in clinical situations whereby interacting with the physician can trigger the mechanisms underlying placebo analgesia with relevant clinical effects [22–24]. Importantly, the results derived from research on placebo analgesia apply also to the nocebo counterpart, whereby negative expectations can elicit increase of pain experience [22, 24–26].

In this review, we present the most recent advances in placebo and nocebo that have been achieved toward neurobiological research. We focus primarily on the brain mechanisms of top-down regulation of sensory processing, the neurochemistry underlying these changes, and the psychological and genetic variables associated with proneness to respond to placebo and nocebo.

Brain, Nociception and Pain Experience

Placebo analgesia produces activity changes and enhanced functional coupling in areas of the brain such as the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC) and subcortical regions including the hypothalamus, amygdala and the periaqueductal grey (PAG) [27–30]. The DLPFC initiates the placebo analgesic response as demonstrated by different groups and approaches [31, 32]. The rACC is connected with the PAG and correlates with the modulation of placebo analgesia [27, 29]. Moreover, placebo analgesia decreases pain-enhanced activity in areas such as the thalamus (Th), insula (INS) and the somatosensory cortex [27, 29, 30, 32], showing a neural correlation with the subjective reduced perception. Recent studies show that the activity at the level of the spinal cord is modulated by placebo analgesia with changes in the ipsilateral dorsal horn, corresponding to the area of stimulation [33]. Using functional magnetic resonance imaging of the human spinal cord, Eippert et al. showed that placebo analgesia results in a reduction of nociceptive processing in the spinal cord suggesting that top-down mechanisms suppress pain processing in the central nervous system at the earliest stages [33].

Notably, the local application of an inert cream on the forearm along with negative suggestions and manipulation of pain intensity increased pain ratings compared with a control cream inducing a nocebo hyperalgesic effect. This nocebo modulation induced a strong activation in the spinal cord at the level of the stimulated dermatomes C5/C6 [34••]. Pain and nocebo effects spatially overlapped and the comparison between pain stimulation under nocebo and control condition showed an enhanced pain-related activity in the ipsilateral dorsal horn of the spinal cord [34••]. These findings emphasize the negative and positive modulatory effects of expectations from frontal areas to the spinal cord extending and corroborating earlier pioneering suggestions and evidence [35–38].

Interestingly, several studies have recently correlated placebo analgesia with brain structure (e.g. grey matter density) and used functional connectivity as a predictor of individual placebo analgesia. Using voxel-based morphometry, Schweinhardt and colleagues found that grey matter density in brain areas such as the DLPFC, INS, and Nucleus Accumbens (NAc) correlated with greater placebo analgesic effects [39]. Structural differences in NAc and DLPFC were in turn correlated with dopamine related traits, including novelty seeking and behavioral activation [39]. It would be interesting to investigate in future studies whether dopamine agonists and antagonists modulate placebo analgesia. More recently, Kong and colleagues investigated how pretest resting-state functional connectivity was linked to expectations and cue-mediated placebo analgesia [40]. An increased baseline resting-state functional connectivity of the right fronto-parietal network with the rostral ACC correlated positively with the magnitude of expectation of analgesia, whilst connectivity between the somatosensory areas and the cerebellum correlated with pain reduction induced by the cues of analgesia [40]. Functional connectivity is also relevant in predicting placebo analgesic responses in patient population. Patients with chronic back pain were studied during a 2-week placebo treatment [41]. The functional connectivity between the dorsomedial PFC and bilateral INSs cortices predicted the magnitude of placebo analgesia and the probability to recover from low back pain. In fact, the patients who responded to the 2-week placebo treatment, showed a lower connectivity between dorsomedial PFC and INSs compared with those who did not respond to placebo and did not recover [41]. Furthermore, patients who recovered from the episode of low back pain under placebo treatment showed a high-frequency activity in the left DLPFC and the midcingulate cortex. The connections between dorsomedial PFC-INS and DLPFC-midcingulate cortex seem to predict the resolution of low back pain with high accuracy (about 90%) [41].

Recently, Stein et al using a tract-finding algorithm that measured local white matter anisotropy and structural connectivity between a priori cortical and subcortical regions of interest, showed that placebo analgesia correlated with higher fractional anisotropy in the rostral ACC and in left DLPFC, and with stronger fiber connections of these 2 regions with the periaqueductal grey (PAG) [42•].

Biochemical Aspects of Placebo Analgesia

The above described findings corroborate the notion that cortical brain regions and their connections to the descending pain inhibitory system including the brainstem are extremely important for endogenous pain modulation. Indeed, expectations induce brain changes by triggering and regulating the interplay of endogenous brain neuropeptides underlying placebo analgesia. It has been extensively demonstrated that placebo analgesia is due to the endogenous release of neuropeptides such as opioids [29], cholecystokinins [43], oxytocin [44], and cannabinoids [15••]. Indirect pharmacologic approaches have provided evidence that placebo analgesia can be antagonized by naloxone thus, indicating that opioids are crucially involved in these kinds of expectancy-driven placebo analgesic effects. The role of the opioidergic system has been confirmed by pharmacologic fMRI and PET studies using an in vivo receptor binding with opioidergic ligands [29, 45, 46]. The placebo analgesia has been also associated with the release of cannabinoids [15••]. In the circumstance in which placebo analgesia is elicited by a non-opioid pharmacologic conditioning with the nonsteroidal anti-inflammatory drug (NSAID) ketorolac, the cannabinoid receptor 1 (CB1) antagonist SR 141716A (rimonabant) blocks placebo analgesia, thus, indicating that the effects elicited by placebo given after NSAID ketorolac are due to the release of endogenous cannabinoids [15••]. Recently, it has been shown that oxytocin agonists given intranasally enhance behavioral placebo analgesia in men [44], suggesting that the oxytocinergic system, which is involved in the modulation of social behaviors [47, 48] might play a role in placebo. Further research is needed to determine whether oxytocin produces similar effects in women, how a dose of oxytocin influences outcomes and what the physiological and brain mechanisms responsible for these effects are.

The nocebo phenomenon is influenced by the cholecystokinin (CCK) system, a system involved in the modulation of anxiety and hyperalgesia. In fact, the block of the CCK A and B receptors with the type A/B receptor antagonist proglumide blocks nocebo hyperalgesia [43].

Genetic Factors

Variation in genetic polymorphisms can to some extent determine the probability of forming a placebo analgesic response and triggering the cascade of events related to placebo-induced reduction of pain [49]. Patients with irritable bowel syndrome (IBS) randomized to no-treatment (‘waitlist’), placebo treatment with a business-like doctor-patient relationship and placebo treatment with an enhanced and supportive doctor-patient relationship were studied. Pain was measured as indicated by the changes from baseline in IBS-Symptom Severity Scale following 3 weeks of treatment, and the number of methionine alleles in the COMT Val158Met polymorphism (rs4633) was considered. Patients with Met/Met alleles had robust placebo analgesic effects and benefited from the enhanced and supportive doctor-patient relationship. Patients with Val/Val alleles minimally benefited from placebo responses and doctor-patient relationship, potentially opening the way to personalized therapeutic approaches [50].

Recently, it has been suggested that a single-nucleotide polymorphism in the fatty acid amide hydrolase (FAAH) gene, C385A (rs324420), that regulates the release of endogenous cannabinoids can be a good predictor of opioid-mediated placebo analgesia [51]. Endogenous cannabinoids and opioids are thought to regulate antinociception synergistically. Zubieta et al examined the link between cannabinoid polymorphisms and μ-opioid mediated placebo analgesia in a positron emission tomography (PET) study using selective radiotracers labeling MOR and D2/3 receptors. The authors found that a μ-opioid-mediated placebo analgesia in regions such as preFC, rostral, dorsal, and subgenual ACC, INS, thalamus, and NAc. Activation of the μ-opioid neurotransmission was also observed in areas associated with reward-motivated learning and memory processing such as the mammillary region, the anterior thalamic nuclei, CC, and hippocampal and parahippocampal gyrus. The endogenous opioid release in these brain areas was significantly correlated with placebo analgesia and FAAH Pro129/Pro129 homozygosity. Interestingly, Pro129/Pro129 homozygotes with lower cannabinoid levels [52], showed higher psychophysical placebo analgesia and regional μ-opioid activation during placebo administration, compared with Pro129/Pro129 heterozygotes [51].

Beyond pain, serotonin-related gene polymorphisms have been found to influence the placebo response in social anxiety, at both the behavioral and neural level [53, 54]. Polymorphisms modulating monoaminergic tone have been linked to the degree of placebo responsiveness in patients with major depressive disorder [55]. It remains a critical need to achieve a deeper understanding of the role of genetic influences in predicting placebo responses in the field of pain and associated disorders (eg, anxiety and depression) at multiple levels including psychometric phenotypes and brain responses. Clarifying the reliability and reproducibility of the genetic predictors represents an important goal both in neuroscience research and for randomized clinical trials.

Psychological Traits

The attempt to find a psychological marker of placebo responsiveness has intrigued researchers for many years, although the results have been quite discouraging. Only recently, psychological traits such as dispositional optimism, hypnotic suggestibility, somatic focus, empathy, neuroticism, altruisms, and the locus of ego-reliance have been linked to placebo analgesia.

Optimism is associated with active behavioral and mental coping when individuals face adversity. Geers and colleagues examined healthy college student participants and their optimistic levels by hypothesizing that optimism is a moderator of placebo responsiveness, thus, a factor that influences the strength and/or direction of the relation between a predictor and placebo analgesia. The authors found that dispositional optimism was correlated with the magnitude of placebo analgesia [56, 57]. These results have been confirmed by the same and other authors [57, 58]. Hypnotic susceptibility, a psychological trait referring to the responsiveness to suggestions influences placebo analgesia [59] and can partially explain inter-individual differences in the neural conditioned placebo analgesic responses in healthy volunteers [60•]. Subjects with high hypnotic susceptibility, showed increased anticipatory activity in a right DLPFC focus, and the ability to reduce functional connectivity of that focus with brain regions related to emotional and evaluative pain processing such as the anterior mid-cingulate cortex and medial PFC. A reverse pattern of fMRI changes and functional connectivity was found in patients with low hypnotic susceptibility [60•].

Somatic focus that refers to the attention toward the body, correlated with larger placebo analgesic effects when pain expectancy was high [61]. Conversely, distraction reduced pain, but did not influence placebo analgesia, thus, suggesting that placebo analgesia and distraction work through distinct mechanisms [61].

Empathy, a vicarious emotion referring to feeling the same emotion as, or congruent with, the emotion of the other person, has also been investigated in the context of placebo research. Specifically, empathy concern of the recipient is a factor that modulates observational placebo analgesia. Interestingly, Colloca et al showed a strong positive correlation between analgesic responses and empathic concern for the live social observation conditions [18]. Most notably, a recent study demonstrated that watching a video modulates placebo analgesia but these video-induced effects were not correlated with dispositional empathy, indicating that empathy is a moderator of observationally-induced placebo analgesia in live interactions only [20].

Personality traits related to dopaminergic function such as novelty seeking, harm avoidance, behavioral drive, fun seeking, and reward responsiveness have been linked with both placebo analgesic effects and gray matter density in the basal ganglia and PFC [39]. More recently, Pecina and colleagues reported that 4 stable personality traits including high Ego-Resiliency, NEO Altruism, NEO Straightforwardness, and low NEO Angry Hostility predicted 25% of placebo responsiveness to pain and 27% of the NAc μ-opioid system activation during placebo administration thus, suggesting a link between behaviors and release of endogenous opioids [62•]. Further research is needed to understand the psychological predictors of nocebo effects, potentially allowing the prediction of unspecific adverse effects in clinical trials and practices [63, 64].

Clinical Pain and Placebo Analgesia

Every treatment is significantly modulated by placebo effects and drug actions and placebo effects interact additively or synergistically depending on the condition. In general, placebo effects seem to act as reinforcers of clinical outcomes. This point is clearly proven by open/hidden models whereby identical concentrations of painkillers are given either covertly or overtly [23]. The former represents the situation in which the treatment is administered by a computer-programmed pump of infusion. The latter is the condition in which the patient is aware of receiving the medication that is administrated by a supportive health practitioner. The clinical response to covert and overt administrations of painkillers is different in terms of time-course reduction of pain. Patients in postoperative acute pain respond much better when their treatments are given by a physician (50% reduction in drug intake) compared with those treated in a socially-deprived context (eg, pump of infusion) [23]. These observations have been extended and corroborated by brain imaging studies showing that the mere awareness of receiving a treatment potentiates the pharmacologic analgesic effect in both healthy patients and patients in postoperative acute pain [65].

Amanzio et al (2001) analyzed the effects of covert and over administration in 4 painkillers that are widely used in clinics and that have distinct mechanisms of action (buprenorphine, tramadol, ketorolac, metamizol) in patients. The analgesic dose needed to reduce the clinical pain by 50% (AD50) was higher with covert than overt infusions for all the classes of painkillers, indicating that the reinforcing effect of expectation is a widespread phenomenon. Amanzio et al (2001) tested the difference between open and hidden injections also in the laboratory setting by using the experimental model of ischemic arm pain in healthy volunteers [66]. Most importantly, the administration of 10 mg of the opiate antagonist, naloxone, reversed the effect of overt administration of ketorolac suggesting that the potentiation is likewise due to the release of endogenous opioids [66].

Placebo Analgesia and Treatment History

Another important aspect to take into account is the link between placebo (and nocebo) effects and the history of treatment in both experimental and clinical settings. Prior positive experiences increase analgesic responses of a subsequent placebo, but negative previous experiences decrease the magnitude of placebo effects. Colloca and Benedetti designed a study in which one group received a simulation of effective treatment (in actuality, the intensity of painful stimulations was surreptitiously decreased) and a second group received a placebo intervention after a treatment perceived as ineffective (verbal suggestions with no manipulation of the intensity of painful stimulation was performed), producing 49.3% vs 9.7% pain reduction, respectively [4]. After a time lag of 4– 7 days, both groups were retested for placebo analgesia. After 4–7 days, the placebo responses following the effective procedure were significantly higher than those observed after the ineffective treatment (29% vs 18% pain reduction). These results indicate that placebo analgesic effects are finely shaped by prior experience (either positive or negative), and that the effect of initial treatment influences the magnitude of subsequent placebo responses even after several days [4].

Similarly, after randomization of healthy patients to two groups, either a positive or negative treatment experience with an inert patch treatment, Kessner et al introduced a new analgesic to test for the effect of treatment history in an fMRI study [67••]. The therapeutic effect of the tested treatment was lower in the negative compared with the positive treatment history group. The adverse effect of the negative treatment history was sustained in the brain by a higher activation of the bilateral posterior INSs, regions related to afferent nociceptive processing, and a lower activation of the right DLPFC that is also involved in nociceptive inhibition processes and placebo analgesia [67••].

The causal relation between amount of previous successful pain relief experiences and placebo analgesia was further demonstrated in another study using a learning model with either 10 or 40 associations between a specific visual cue and analgesic experience [68]. The persistence of placebo and nocebo responses was firmly connected to the length of exposures to prior effective (and ineffective) interventions, thus, demonstrating that the size and the resistance to extinction of the ensuing placebo and nocebo responses is intrinsically connected with the number of conditioning trials [68].

It is interesting to consider how these concepts may apply to clinical contexts. For example, André-Obadia et al showed that the magnitude of placebo analgesia in patients with chronic neuropathic pain depended on prior exposure to either successful or unsuccessful treatment [69]. The placebo analgesia of repetitive transcranial magnetic stimulation (rTMS) was evaluated in a cross-over study design in which neuropathic pain patients resistant to pharmacologic treatment were assigned to one of two arms—sham rTMS delivered either before or after the conventional stimulation of the motor cortex. Carry-over effects of a single session of rTMS did not exceed a week. Those patients who received the sham rTMS after a session of real rTMS perceived an analgesic effect (11% pain reduction). By contrast, patients who received the sham session after the ineffective rTMS intervention experienced higher levels of pain (6% pain increase), indicating that the exposure to effective treatments induces the formation of analgesic placebo responses that are stronger compared with responses following placebos given first [69]. These findings are in line with the pioneering results by Laska et al suggesting the existence of a dose-response relationship between the delivery of the first medication and the response to a subsequent placebo.

Overall these studies seem to support the fact that positive and negative previous therapeutic experiences may confound the results of cross-over designs. Clinically speaking, it is worth appreciating that learned placebo analgesic effects can be elicited in patients suffering from neuropathic pain despite the fact that the pain was refractory to conventional pharmacologic interventions. These findings deserve further investigation for the potential to improve the design of clinical trials and likewise, optimize therapeutic strategies.

Conclusions

Current knowledge of placebo and nocebo effects provides direct evidence for a pain-inhibiting or facilitating mechanism in the human brain and spinal cord, which can be activated by cognitive manipulations of expectations through verbal suggestions, pharmacologic, and nonpharmacologic conditioning, and social learning. Brain changes are strategically linked to the release of endogenous opioids, cannabinoids, and CCKs. Psychological and genetic traits are likely to contribute to the occurrence of these inner processes potentially helping predict individuals who may activate these inner processes. More research is needed to expand this evidence to different kinds of pain and conditions associated with clinical pain. Fruitful research in this field is likely to improve personalized therapeutic approaches to pain management.

Acknowledgments

Footnotes

References

Papers of particular interest, published recently, have been highlighted as:

• Of importance

•• Of major importance

1••. Colloca L, Flaten MA, Meissner K.  Placebo and Pain: From bench to bedside. Elsevier; Oxford, UK: 2013. This book is the first comprehensive presentation of the placebo and nocebo phenomena in the area of pain and integrates a broad range of contributions discussing: (a) historical and methodological aspects of the placebo/nocebo effects; (b) biological and psychological mechanisms of placebo analgesia and nocebo hyperlagesia; and (c), implications of the placebo and nocebo effects for clinical research and pain management.

2•. Colloca L, Klinger R, Flor H, Bingel U. Placebo analgesia: psychological and neurobiological mechanisms. Pain. 2013;154:511–4. This review article provides an accurate and succinct up-to-date report on current knowledge regarding the neurobiological aspects of placebo-induced modulation of pain. [PMC free article]  [PubMed]

3. Colloca L, Miller FG. Role of expectations in health. Curr Opin Psychiatr. 2011;24:149–55.  [PubMed]

4. Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain. 2006;124:126–33.[PubMed]

5. Colloca L, Miller FG. How placebo responses are formed: a learning perspective. Philos Trans R Soc Lond B Biol Sci. 2011;366:1859–69. [PMC free article]  [PubMed]

6. Colloca L, Sigaudo M, Benedetti F. The role of learning in nocebo and placebo effects. Pain. 2008;136:211–8.  [PubMed]

7. Colloca L, Tinazzi M, Recchia S, Le Pera D, Fiaschi A, Benedetti F, et al. Learning potentiates neurophysiological and behavioral placebo analgesic responses. Pain. 2008;139:306–14.  [PubMed]

8. 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;128:31–9.  [PubMed]

9. Voudouris NJ, Peck CL, Coleman G. The role of conditioning and verbal expectancy in the placebo response. Pain. 1990;43:121–8.  [PubMed]

10. Fiorio M, et al. Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation. Neuroscience. 2012;217:96–104.  [PubMed]

11. Fiorio M, Recchia S, Corra F, Tinazzi M. Behavioral and neurophysiological investigation of the influence of verbal suggestion on tactile perception. Neuroscience. 2014;258:332–9.  [PubMed]

12. Jensen KB, Kaptchuk TJ, Kirsch I, Raicek J, Lindstrom KM, Berna C, et al. Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci U S A. 2012;109:15959–64. [PMC free article][PubMed]

13. Colloca L, Miller FG. Harnessing the placebo effect: the need for translational research. Philos Trans R Soc Lond B Biol Sci. 2011;366:1922–30. [PMC free article]  [PubMed]

14. Amanzio M, Benedetti F. Neuropharmacologic dissection of placebo analgesia: expectation-activated opioid systems vs conditioning-activated specific subsystems. J Neurosci. 1999;19:484–94.  [PubMed]

15••. Benedetti F, Amanzio M, Rosato R, Blanchard C. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med. 2011;17:1228–30. This article is the first indirect pharmacologic evidence that the cannabinoid system accounts for placebo analgesic responses together with the opioid system. [PubMed]

16. Benedetti F, Pollo A, Colloca L. Opioid-mediated placebo responses boost pain endurance and physical performance: is it doping in sport competitions? J Neurosci. 2007;27:11934–9.  [PubMed]

17. Guo JY, Wang JY, Luo F. Dissection of placebo analgesia in mice: the conditions for activation of opioid and non-opioid systems. J Psychopharmacol. 2010;24:1561–7.  [PubMed]

18. Colloca L, Benedetti F. Placebo analgesia induced by social observational learning. Pain. 2009;144:28–34.  [PubMed]

19. Swider K, Babel P. The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning. Pain. 2013;154:1312–7.  [PubMed]

20. Hunter T, Siess F, Colloca L. Socially induced placebo analgesia: A comparison of a pre-recorded vs live face-to-face observation. Eur J Pain. 2013 doi:10.1002/j.1532-2149.2013.00436.x. [PMC free article][PubMed]

21. Vogtle E, Barke A, Kroner-Herwig B. Nocebo hyperalgesia induced by social observational learning. Pain. 2013;154:1427–33.  [PubMed]

22. Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev. 2013;93:1207–46. [PMC free article]  [PubMed]

23. Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt vs covert treatment for pain, anxiety, and Parkinson’s disease. Lancet Neurol. 2004;3:679–84.  [PubMed]

24. Miller FG, Colloca L, Kaptchuk TJ. The placebo effect: illness and interpersonal healing. Perspect Biol Med. 2009;52:518–39. [PMC free article]  [PubMed]

25. Colloca L, Miller FG. The nocebo effect and its relevance for clinical practice. Psychosom Med. 2011;73:598–603. [PMC free article]  [PubMed]

26. Benedetti F, Lanotte M, Lopiano L, Colloca L. When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience. 2007;147:260–71.  [PubMed]

27. Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain. 2006;120:8–15.  [PubMed]

28. Craggs JG, Price DD, Perlstein WM, Verne GN, Robinson ME. The dynamic mechanisms of placebo induced analgesia: evidence of sustained and transient regional involvement. Pain. 2008;139:660–9.[PMC free article]  [PubMed]

29. Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63:533–43.  [PubMed]

30. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 2004;303:1162–7.  [PubMed]

31. Krummenacher P, Candia V, Folkers G, Schedlowski M, Schonbachler G. Prefrontal cortex modulates placebo analgesia. Pain. 2010;148:368–74.  [PubMed]

32. Lui F, Colloca L, Duzzi D, Anchisi D, Benedetti F, Porro CA. Neural bases of conditioned placebo analgesia. Pain. 2010;151:816–24.  [PubMed]

33. Eippert F, Finsterbusch J, Bingel U, Buchel C. Direct evidence for spinal cord involvement in placebo analgesia. Science. 2009:326–404.  [PubMed]

34••. Geuter S, Buchel C. Facilitation of pain in the human spinal cord by nocebo treatment. J Neurosci. 2013;33:13784–90. his article provides evidence that nocebo manipulations leads to increased pain perception, lowered pain thresholds, and increased BOLD activity in the spinal corn. The peak activation in the ipsilateral spinal cord was at the same rostro-caudal level as shown in a twin previous study by Eippert et al (2009), in which placebo manipulations were used. Together these studies corroborate the notion that placebo and nocebo modulate pain bidirectionally at the level of the spinal cord.  [PubMed]

35. Fields HL. Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res. 2000;122:245–53.  [PubMed]

36. Fields HL, Levine JD. Biology of placebo analgesia. Am J Med. 1981;70:745–6.  [PubMed]

37. Levine JD, Gordon NC, Bornstein JC, Fields HL. Role of pain in placebo analgesia. Proc Natl Acad Sci U S A. 1979;76:3528–31. [PMC free article]  [PubMed]

38. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet. 1978;2:654–7.[PubMed]

39. Schweinhardt P, Seminowicz DA, Jaeger E, Duncan GH, Bushnell MC. The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response. J Neurosci. 2009;29:4882–7.  [PubMed]

40. Kong J, Jensen K, Loiotile R, Cheetham A, Wey H-Y, Tan Y, et al. Functional connectivity of the fronto-parietal network predicts cognitive modulation of pain. Pain. 2013;154:459–67. [PMC free article][PubMed]

41. Hashmi JA, et al. Brain networks predicting placebo analgesia in a clinical trial for chronic back pain. Pain. 2012;153:2393–402. [PMC free article]  [PubMed]

42•. 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;153:2210–7. The authors demonstrate that structural connectivity indexed by fractional anisotropy correlates with placebo analgesic responses. Positive correlations between the fractional anisotropy and individual placebo analgesic responses were found in the dorsalateral prefrontal cortex, left rostral anterior cingulate cortex, and the periacqueductal gray. The white matter integrity within and between regions of the descending pain modulatory network is crucially linked to the placebo-induced control of pain. [PubMed]

43. Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci. 2006;26:12014–22.  [PubMed]

44. Kessner S, Sprenger C, Wrobel N, Wiech K, Bingel U. Effect of oxytocin on placebo analgesia: a randomized study. JAMA. 2013;310:1733–5.  [PubMed]

45. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci U S A. 2007;104:11056–61. [PMC free article]  [PubMed]

46. Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 2005;25:7754–62.  [PubMed]

47. Campbell A. Oxytocin and human social behavior. Pers Soc Psychol Rev. 2010;14:281–295.  [PubMed]

48. Heinrichs M, Domes G. Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. Prog Brain Res. 2008;170:337–50.  [PubMed]

49. Hall KT, Kaptchuk TJ. Genetic biomarkers of placebo response: what could it mean for future trial design? Clin Investig. 2013;3:11–314. [PMC free article]  [PubMed]

50. Hall KT, Lembo AJ, Kirsch I, Ziogas DC, Douaiher J, Jensen KB, et al. Catechol-O-Methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome. PLoS One. 2012;7:e48135.[PMC free article]  [PubMed]

51. Pecina M, et al. FAAH selectively influences placebo effects. Mol Psychiatr. 2013;19:385–91.[PubMed]

52. Chiang KP, Gerber AL, Sipe JC, Cravatt BF. Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet. 2004;13:2113–9.  [PubMed]

53. Faria V, Appel L, Ahs F, Linnman C, Pissiota A, Frans O, et al. Amygdala subregions tied to SSRI and placebo response in patients with social anxiety disorder. Neuropsychopharmacology. 2012;37:2222–32.[PMC free article]  [PubMed]

54. Furmark T, Appel L, Henningsson S, Ahs F, Faria V, Linnman C, et al. A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J Neurosci. 2008;28:13066–74.  [PubMed]

55. Leuchter AF, McCracken JT, Hunter AM, Cook IA, Alpert JE. Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. J Clin Psychopharmacol. 2009;29:372–7.  [PubMed]

56. Geers AL, Helfer SG, Kosbab K, Weiland PE, Landry SJ. Reconsidering the role of personality in placebo effects: dispositional optimism, situational expectations, and the placebo response. J Psychosom Res. 2005;58:121–7.  [PubMed]

57. Geers AL, Wellman JA, Fowler SL, Helfer SG, France CR. Dispositional optimism predicts placebo analgesia. J Pain. 2010;11:1165–71. [PMC free article]  [PubMed]

58. Morton DL, Watson A, El-Deredy W, Jones AK. Reproducibility of placebo analgesia: effect of dispositional optimism. Pain. 2009;146:194–8.  [PubMed]

59. De Pascalis V, Chiaradia C, Carotenuto E. The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting. Pain. 2002;96:393–402.  [PubMed]

60•. Huber A, Lui F, Porro CA. Hypnotic susceptibility modulates brain activity related to experimental placebo analgesia. Pain. 2013;154:1509–18. The authors report that hypnotic susceptibility is linked to placebo analgesia from a brain imaging perspective. During the anticipatory phase, patients with higher hypnotic susceptibility showed increased anticipatory activity in a right dorsolateral prefrontal cortex and a reduction in functional connectivity within brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex). Subjects with lower hypnotic susceptibility showed an opposite pattern of fMRI activity and functional connectivity. During placebo-induced analgesia, activity in the regions reflecting attention/arousal (bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral posterior temporal foci) was negatively related to analgesic placebo responses in patients with higher hypnotic susceptibility.  [PubMed]

61. Johnston NE, Atlas LY, Wager TD. Opposing effects of expectancy and somatic focus on pain. PLoS One. 2012;7:e38854. [PMC free article]  [PubMed]

62•. Pecina M, Azhar H, Love TM, Lu T, Fredrickson BL, Stohler CS, et al. Personality trait predictors of placebo analgesia and neurobiological correlates. Neuropsychopharmacology. 2013;38:639–46. This article outlines that some psychological traits trigger the μ-opioid-mediated placebo analgesia. Specifically, ego-resiliency, NEO Altruism, NEO Straightforwardness (positive predictors), and NEO Angry Hostility (negative predictor) traits account for 25% of the variance in the release of endogenous μ-opioids during placebo analgesia. [PMC free article]  [PubMed]

63. Colloca L, Benedetti F. Nocebo hyperalgesia: how anxiety is turned into pain. Curr Opin Anaesthesiol. 2007;20:435–9.  [PubMed]

64. Colloca L, Finniss D. Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA. 2012;307:567–8.  [PubMed]

65. Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011;3:70ra14.  [PubMed]

66. Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain. 2001;90:205–15.  [PubMed]

67••. Kessner S, Wiech K, Forkmann K, Ploner M, Bingel U. The effect of treatment history on therapeutic outcome: an experimental approach. JAMA Intern Med. 2013:1–2. On days 1 and 2, either a positive or negative treatment experience was induced by combining an inert patch treatment with a conditioning manipulation. Functional magnetic resonance imaging responses were used as a physiological marker of placebo-induced analgesia. The authors found a weaker reduction of pain-related activity in the posterior insula in the negative compared with the positive treatment history group, thus, indicating the treatment history shapes behavioral and brain responses to pain experience.  [PubMed]

68. Colloca L, Petrovic P, Wager TD, Ingvar M, Benedetti F. How the number of learning trials affects placebo and nocebo responses. Pain. 2010;151:430–9. [PMC free article]  [PubMed]

69. Andre-Obadia N, Magnin M, Garcia-Larrea L. On the importance of placebo timing in rTMS studies for pain relief. Pain. 2011;152:1233–7.  [PubMed]