Effects of Oxytocin on Placebo and Nocebo Effects in a Pain Conditioning Paradigm: A Randomized Controlled Trial

Oxytocin has been shown to increase trust, decrease anxiety, and affect learning as has been observed in conditioning paradigms. Trust, anxiety, and learning are important factors that influence placebo effects. In this study, we investigated whether oxytocin can increase placebo analgesia, decrease nocebo hyperalgesia, and influence extinction processes of both. Eighty male volunteers were assigned to a 40 IU of oxytocin nasal spray group, or to a placebo control group. Placebo analgesia and nocebo hyperalgesia were induced by a conditioning procedure in combination with verbal suggestions. The results demonstrate that the conditioning procedure successfully elicited significant placebo analgesia and nocebo hyperalgesia responses (P < .001). Furthermore, extinction was observed (P < .001), although placebo and nocebo responses did not return to baseline and remained significant. Oxytocin did not influence placebo analgesia or nocebo hyperalgesia and had no effect on extinction. This study provides support against the placebo-boosting effects of oxytocin and was the first one to demonstrate that it also did not influence nocebo effects or extinction processes, however, these results pertain to only a male sample. As managing placebo and nocebo effects has widespread clinical implications, further research should investigate other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects.PerspectiveThe present study demonstrated that placebo analgesia and nocebo hyperalgesia can be successfully induced by conditioning and verbal suggestions. We could not confirm the hypothesis that oxytocin affects either of these phenomena. Other pharmacological agents and behavioral manipulations for increasing placebo and decreasing nocebo effects should be investigated.     

Efficacy of open-label counterconditioning for reducing nocebo effects on pressure pain

Background

Nocebo effects can adversely affect the experience of physical symptoms, such as pain and itch. Nocebo effects on itch and pain have shown to be induced by conditioning with thermal heat stimuli and reduced by counterconditioning. However, open-label counterconditioning, in which participants are informed about the placebo content of the treatment, has not been investigated, while this can be highly relevant for clinical practice. Furthermore, (open-label) conditioning and counterconditioning has not been investigated for pain modalities relevant to musculoskeletal disorders, such as pressure pain.

Methods

In a randomized controlled trial, we investigated in 110 healthy female participants whether nocebo effects on pressure pain combined with open-label verbal suggestions can be (1) induced via conditioning and (2) reduced via counterconditioning. Participants were allocated to either a nocebo- or sham-conditioning group. Next, the nocebo group was allocated to either counterconditioning, extinction or continued nocebo conditioning; sham conditioning was followed by placebo conditioning.

Results

Nocebo effects were significantly larger after nocebo conditioning than sham conditioning (d = 1.27). Subsequently, a larger reduction of the nocebo effect was found after counterconditioning than after extinction (d = 1.02) and continued nocebo conditioning (d = 1.66), with effects similar to placebo conditioning (following sham conditioning).

Conclusions

These results show that (counter)conditioning combined with open-label suggestions can modulate nocebo effects on pressure pain, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders, particularly for musculoskeletal disorders.

Significance

Few studies have investigated the efficacy counterconditioning to reduce nocebo effects. Whereas typically deceptive procedures are used, these are not ethically appropriate for use in clinical practice. The current study demonstrates that open-label counterconditioning in a pain modality relevant for many chronic pain conditions may be a promising new strategy for reducing nocebo effects in a non-deceptive and ethical manner, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders.     

Pre-Exposure,But Not Overshadowing,Inhibits Nocebo Hyperalgesia

Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies – overshadowing (Experiment 1) and pre-exposure (Experiment 2) – could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode ‘activated’, which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings.PerspectiveNocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.     

The role of learning in nocebo and placebo effects

The nocebo effect consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Here we show that nocebo suggestions, in which expectation of pain increase is induced, are capable of producing both hyperalgesic and allodynic responses. By extending previous findings on the placebo effect, we investigated the role of learning in the nocebo effect by means of a conditioning procedure. To do this, verbal suggestions of pain increase were given to healthy volunteers before administration of either tactile or low-intensity painful electrical stimuli. This nocebo procedure was also carried out after a pre-conditioning session in which two different conditioned visual stimuli were associated to either pain or no-pain. Pain perception was assessed by means of a Numerical Rating Scale raging from 0 = tactile to 10 = maximum imaginable pain. We found that verbal suggestions alone, without prior conditioning, turned tactile stimuli into pain as well as low-intensity painful stimuli into high-intensity pain. A conditioning procedure produced similar effects, without significant differences. Therefore, in contrast to placebo analgesia, whereby a conditioning procedure elicits larger effects compared to verbal suggestions alone, learning seems to be less important in nocebo hyperalgesia. Overall, these findings indicate that, by defining hyperalgesia as an increase in pain sensitivity and allodynia as the perception of pain in response to innocuous stimulation, nocebos can indeed produce both hyperalgesic and allodynic effects. These results also suggest that learning is not important in nocebo hyperalgesia compared to placebo analgesia.     

Instrumental Control Enhances Placebo Analgesia

Placebo analgesia is a robust phenomenon readily observed in both experimental and clinical settings. While researchers have begun to unpack its psychobiological mechanisms, important questions remain regarding how we can capitalize on the placebo effect to improve clinical pain outcomes. The current study tested whether providing individuals with instrumental control—that is, control over if and when they administer a treatment—is capable of enhancing placebo analgesia. Using an established electrocutaneous pain design, 87 healthy volunteers either received placebo conditioning with instrumental control over treatment administration, standard passive placebo conditioning without any control over treatment administration, or were allocated to natural history control group with no conditioning and were later tested at equivalent shock intensity with and without placebo applied. Both placebo groups demonstrated initial placebo analgesia. Importantly, however, those provided with instrumental control demonstrated significantly larger and longer lasting placebo analgesia as well as reduced anticipatory autonomic arousal than those receiving standard passive placebo conditioning. This suggests that providing instrumental control over treatment administration can facilitate placebo analgesia by enhancing its magnitude and durability. As such, providing instrumental control over treatment administration may be a cheap and ethical method of using the placebo effect to improve clinical pain outcomes.PerspectivePlacebo research typically involves passive designs where individuals have no control over treatment administration. We present novel data demonstrating that providing control over treatment administration substantially enhances both the magnitude and duration of placebo analgesia. As such, where possible, providing control may improve clinical pain outcomes via the placebo effect.     

The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning

Research shows that placebo analgesia can be induced through social observational learning. Our aim was to replicate and extend this result by studying the effect of the sex of both the model and the subject on the magnitude of placebo analgesia induced by social observational learning. Four experimental (1 through 4) and 2 control (5 and 6) groups were observed: groups 1, 3, and 5 were female; groups 2, 4, and 6 were male. All subjects received pain stimuli of the same intensity preceded by green and red lights. Before receiving pain stimuli, groups 1 and 4 observed a female model and groups 2 and 3 a male model; both models simulated responses to pain stimuli preceded by green lights as less painful than those preceded by red lights. Groups 1 through 4 also rated pain stimuli preceded by green lights as less painful. Further investigation revealed that in fact subjects in experimental groups rated red-associated stimuli as more painful than subjects from control groups who did not observe a model before receiving the same pain stimuli, indicating that nocebo hyperalgesia rather than placebo analgesia was induced. Empathy traits predicted the magnitude of nocebo hyperalgesia. Regardless of the sex of the subject, nocebo hyperalgesia was greater after the male model was observed. The results show that social observational learning is a mechanism that produces placebo effects. They also indicate that the sex of the model plays an important role in this process.     

How the number of learning trials affects placebo and nocebo responses

Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.     

Partial reinforcement,extinction, and placebo analgesia

Numerous studies indicate that placebo analgesia can be established via conditioning procedures. However, these studies have exclusively involved conditioning under continuous reinforcement. Thus, it is currently unknown whether placebo analgesia can be established under partial reinforcement and how durable any such effect would be. We tested this possibility using electrocutaneous pain in healthy volunteers. Sixty undergraduates received placebo treatment (activation of a sham electrode) under the guise of an analgesic trial. The participants were randomly allocated to different conditioning schedules, namely continuous reinforcement (CRF), partial reinforcement (PRF), or control (no conditioning). Conditioning was achieved by surreptitiously reducing pain intensity during training when the placebo was activated compared with when it was inactive. For the CRF group, the placebo was always followed by a surreptitious reduction in pain during training. For the PRF group, the placebo was followed by a reduction in pain stimulation on 62.5% of trials only. In the test phase, pain stimulation was equivalent across placebo and no placebo trials. Both CRF and PRF produced placebo analgesia, with the magnitude of initial analgesia being larger after CRF. However, although the placebo analgesia established under CRF extinguished during test phase, the placebo analgesia established under PRF did not. These findings indicate that PRF can induce placebo analgesia and that these effects are more resistant to extinction than those established via CRF. PRF may therefore reflect a novel way of enhancing clinical outcomes via the placebo effect.     

Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

The neural mechanisms whereby placebo conditioning leads to placebo analgesia remain unclear. In this study we aimed to identify the brain structures activated during placebo conditioning and subsequent placebo analgesia. We induced placebo analgesia by associating a sham treatment with pain reduction and used fMRI to measure brain activity associated with three stages of the placebo response: before, during and after the sham treatment, while participants anticipated and experienced brief laser pain. In the control session participants were explicitly told that the treatment was inactive. The sham treatment group reported a significant reduction in pain rating (p = 0.012). Anticipatory brain activity was modulated during placebo conditioning in a fronto-cingulate network involving the left dorsolateral prefrontal cortex (DLPFC), medial frontal cortex and the anterior mid-cingulate cortex (aMCC). Identical areas were modulated during anticipation in the placebo analgesia phase with the addition of the orbitofrontal cortex (OFC). However, during altered pain experience only aMCC, post-central gyrus and posterior cingulate demonstrated altered activity. The common frontal cortical areas modulated during anticipation in both the placebo conditioning and placebo analgesia phases have previously been implicated in placebo analgesia. Our results suggest that the main effect of placebo arises from the reduction of anticipation of pain during placebo conditioning that is subsequently maintained during placebo analgesia.     

Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions

Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up-like pain). There was a significant placebo effect on both ongoing (P = .009 to .019) and evoked neuropathic pain (P = .0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P ⩽ .001). Pain increases during nocebo were nonsignificant (P = .394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients’ expectations coexist with emotional feelings about treatments.     

Enhanced affect/cognition-related brain responses during visceral placebo analgesia in irritable bowel syndrome patients

Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patients with irritable bowel syndrome (IBS) exhibit visceral hyperalgesia and heightened affective/cognitive brain region activation during visceral stimuli. Psychological factors alter the pain and brain activation pattern, and these changes are more pronounced in IBS patients. Expectation constitutes the major neuropsychological mechanism in the placebo effect. This study confirmed the heightened affective/cognitive brain responses in IBS patients during visceral placebo analgesia using a placebo model with expectation, which was enhanced by suggestion and conditioning. Seventeen IBS patients and 17 age-/sex-matched controls were enrolled. Psychophysical inventories (Hospital Anxiety and Depression Scale [HADS], visual analogue scale, and short-form McGill questionnaire) were completed. Brain activity during placebo intervention and anticipation was assessed in response to rectal distension using 3T-functional magnetic resonance imaging. Suggestion-/conditioning-enhanced placebo was used to convince controls/patients of the efficacy of a newly developed intravenous drug (saline, in actuality) for the relief of rectal distension-induced visceral pain. A comparable visceral placebo analgesia was observed in IBS patients and control subjects. IBS patients demonstrated a higher HADS-anxiety score, which was predictive of a weak placebo effect. Suggestion-/conditioning-enhanced placebo evoked more activity in affective/cognitive brain regions (insula, midcingulate cortex, and ventrolateral prefrontal cortex [VLPFC]) in IBS patients than in healthy controls. VLPFC was also more active during anticipation in IBS patients. In conclusion, IBS patients and control subjects achieved comparable placebo analgesia during experimentally induced rectal pain. The visceral placebo analgesia produced heightened activity in affective/cognitive brain regions in IBS patients.     

Placebo Analgesia From a Rubber Hand

Placebo analgesia, reductions in pain after administration of an inert treatment, is a well documented phenomenon. We report, to our knowledge, the first demonstration that placebo analgesia can be experienced when a sham analgesic is applied onto a rubber hand. The effect was obtained by exploiting the rubber hand illusion, in which ownership is felt over a rubber arm that is unattached to the body. Under conditions of synchronous as well as asynchronous visuotactile stimulation, a thermal pain stimulus was delivered on the real arm of 20 participants and seemingly also on the rubber arm, before and after applying a sham analgesic and a control cream only to the rubber arm. During synchronous visuotactile stimulation, pain was experienced on the rubber arm, and the application of the sham analgesic to the rubber arm significantly decreased the severity of reported pain. This shows that experience of the body can modulate expectations and the induction of placebo analgesia.

Neural bases of conditioned placebo analgesia

Despite growing interest in the placebo effect, the neural correlates of conditioned analgesia are still incompletely understood. We investigated herein on brain activity during the conditioning and post-conditioning phases of a placebo experimental paradigm, using event-related fMRI in 31 healthy volunteers. Brief laser heat stimuli delivered to one foot (either right or left) were preceded by different visual cues, signalling either painful stimuli alone, or painful stimuli accompanied by a (sham) analgesic procedure. Cues signalling the analgesic procedure were followed by stimuli of lower intensity in the conditioning session, whereas in the test session both cues were followed by painful stimuli of the same intensity. During the first conditioning trials, progressive signal increases over time were found during anticipation of analgesia compared to anticipation of pain, in a medial prefrontal focus centered on medial area BA8, and in bilateral lateral prefrontal foci. These frontal foci were adjacent to, and partially overlapped, those active during anticipation of analgesia in the test session, whose signal changes were related to the magnitude of the placebo behavioral response, and those active during placebo analgesia. Specifically, a large focus in the right prefrontal cortex showed activity related to analgesia, irrespective of the expected side of stimulation. Analgesia was also related to decreased activity, detectable immediately following noxious stimulation, in parietal, insular and cingulate pain-related clusters. Our findings of dynamic changes in prefrontal areas during placebo conditioning, and of direct placebo effects on cortical nociceptive processing, add new insights into the neural bases of conditioned placebo analgesia.     

The Acquisition and Extinction of Fear of Painful Touch: A Novel Tactile Fear Conditioning Paradigm

Fear of touch, due to allodynia and spontaneous pain, is not well understood. Experimental methods to advance this topic are lacking, and therefore we propose a novel tactile conditioning paradigm. Seventy-six pain-free participants underwent acquisition in a predictable as well as an unpredictable pain context. In the predictable context, vibrotactile stimulation was paired with painful electrocutaneous stimulation (simulating allodynia). In the unpredictable context, vibrotactile stimulation was unpaired with pain (simulating spontaneous pain). During an extinction phase, a cue exposure and context exposure group continued in the predictable and unpredictable context, respectively, without pain. A control group received continued acquisition in both contexts. Self-reported fear and skin conductance responses, but not startle responses, showed fear of touch was acquired in the predictable context. Context-related startle responses showed contextual fear emerged in the unpredictable context, together with elevated self-reported fear and skin conductance responses evoked by the unpaired vibrotactile stimulations. Cue exposure reduced fear of touch, whereas context exposure reduced contextual fear. Thus, painful touch leads to increased fear, as does touch in the same context as unpredictable pain, and extinction protocols can reduce this fear. We conclude that tactile conditioning is valuable for investigating fear of touch and can advance our understanding of chronic pain.

Placebo and nocebo effects on itch: effects,mechanisms, and predictors

Placebo and nocebo effects have been extensively studied in the field of pain and more recently also on itch. In accordance with placebo research on pain, expectancy learning via verbal suggestion or conditioning has shown to induce placebo and nocebo effects on itch, in which the combination of both procedures seems most promising. Moreover, itch can also be transferred ‘contagiously’ in which suggestion and social behavioural learning seem to play a role. With regard to predictors of placebo and nocebo responding on itch and contagious itch, preliminary evidence suggests a role for individual psychological characteristics and personality traits regarding negative outcome expectancies. Although findings on placebo and nocebo effects on itch seem comparable to pain, we have only just begun to understand the underlying mechanisms and predictors of placebo and nocebo effects on itch.     

Cognitive manipulation targeted at decreasing the conditioning pain perception reduces the efficacy of conditioned pain modulation

Although painfulness of the conditioning stimulus (CS) is required for the activation of conditioned pain modulation (CPM), it is still unclear whether CPM expression depends on the objective physical intensity of the CS or the subjective perception of its pain. Accordingly, we cognitively manipulated the perceived CS pain, rendering the physical aspects of the CPM paradigm untouched. Baseline CPM was measured among 48 young healthy male subjects using the parallel paradigm with contact heat as test pain and hand immersion in hot water as CS. Subjects were then randomized into 4 groups, all of which were cognitively manipulated as to the CS-induced pain: group 1, placebo (CS less painful); group 2, nocebo (CS more painful); and groups 3 and 4, the informed control groups for groups 1 and 2, respectively. CPM was reassessed after the manipulation. Comparing the groups by MANCOVA (multivariate analysis of covariance) revealed that placebo exerted decreased CS pain and consequent attenuation of CPM magnitudes, while nocebo elicited increased CS pain, but without CPM elevation (P < .0001). Within the placebo group, the reduction in CS pain was associated with diminished CPM responses (r = 0.767; P = .001); however, no such relationship characterized the nocebo group. Pain inhibition under CPM seems to depend on the perceived level of the CS pain rather than solely its physical intensity. Cognitively decreasing the perceived CS pain attenuates CPM magnitude, although a ceiling effect may limit CPM enhancement after cognitively increased CS pain. These findings emphasize the relevance of cognitive mechanisms in determining endogenous analgesia processes in humans.     

Placebo manipulations reduce hyperalgesia in neuropathic pain

Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R(2)=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.     

Seeing facial expressions enhances placebo analgesia

The strength of the placebo effect is influenced by social contexts and individual personality. Although facial expressions provide important contextual cues, no study of their influence on the placebo response has been performed hitherto. Here we tested (1) whether the observation of facial expressions with different emotional content (Neutral, Pain, and Happy) affects the magnitude of placebo analgesia, and (2) whether interindividual differences in personality traits interact with any modulation of placebo response induced by facial expression. Twenty-seven healthy participants underwent classical placebo conditioning, and subsequently rated the intensity and unpleasantness of their pain experience associated with nociceptive-specific laser pulses delivered to the right hand dorsum. On each trial, different visual cues signalled the occurrence of a laser stimulus alone or of a laser stimulus accompanied by a sham analgesic treatment. In the conditioning period, cues signalling the sham treatment were followed by laser stimuli whose intensity was surreptitiously lowered. In the test period, either cue was followed by laser stimuli of the same intensity. The observation of facial expressions with different emotional content enhanced significantly the placebo analgesia. In particular, a significantly greater analgesic effect was observed when facial expressions with emotional content were presented concomitantly to the nociceptive stimulation. The enhancement of placebo analgesia during the observation of facial expressions was not correlated with personality traits like empathy and behavioural activation/inhibition. These findings quantify for the first time the effect of facial expressions on the magnitude of placebo analgesia.     

Neural mechanisms mediating positive and negative treatment expectations in visceral pain: A functional magnetic resonance imaging study on placebo and nocebo effects in healthy volunteers

To elucidate placebo and nocebo effects in visceral pain, we conducted a functional magnetic resonance imaging (fMRI) study to analyze effects of positive and negative treatment expectations in a rectal pain model. In 36 healthy volunteers, painful rectal distensions were delivered after intravenous application of an inert substance combined with either positive instructions of pain relief (placebo group) or negative instructions of pain increase (nocebo group), each compared to neutral instructions. Neural activation during cued-pain anticipation and pain was analyzed along with expected and perceived pain intensity. Expected and perceived pain intensity were significantly increased in the nocebo group and significantly decreased in the placebo group. In the placebo group, positive expectations significantly reduced activation of the somatosensory cortex during anticipation and of the insula, somatosensory cortex, and amygdala during pain delivery when compared to neutral expectations. Within the nocebo group, negative expectations led to significantly increased insula activation during painful stimulation. Direct group contrasts during expectation modulation revealed significantly increased distension-induced activation within the somatosensory cortex in the nocebo group. In conclusion, the experience and neural processing of visceral pain can be increased or decreased by drug-specific expectations. This first brain imaging study on nocebo effects in visceral pain has implications for the pathophysiology and treatment of patients with chronic abdominal complaints such as irritable bowel syndrome.     

The Influence of Placebo Analgesia Manipulations on Pain Report,the Nociceptive Flexion Reflex,and Autonomic Responses to Pain

Expectations for pain relief and experience/conditioning are psychological factors that contribute to placebo analgesia, yet few studies have studied the physiological mechanisms underlying their effects. This study randomized 133 participants to 4 groups: an expectation only (E-only) group, a conditioning only (C-only) group, an expectation plus conditioning (E+C) group, and a natural history (NH) control group. Painful electric stimulations were delivered before and after an inert cream was applied to the site of stimulation. Pain-related outcomes (pain ratings, nociceptive flexion reflex [NFR], skin conductance response, and heart rate acceleration) were recorded after each stimulation. NFR (a measure of spinal nociception) assessed if placebo analgesia inhibited spinal processing of pain. E+C was the only manipulation that significantly inhibited pain and skin conductance response. Surprisingly, NFR was facilitated in the E+C and E-only groups. No effects were noted for C-only. Mediation analysis suggested 2 descending processes were engaged during E+C that influenced spinal nociception: 1) descending facilitation and 2) descending inhibition that was also responsible for pain reduction. These results suggest that E+C manipulations produce the strongest analgesia and have a complex influence on spinal nociception involving both inhibitory and facilitatory processes.