Placebo Analgesic Effect Research Articles

Placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease and healthy participants.

The role of placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease (AD) is largely unknown, with only few studies in the area. Therefore, this study aims to investigate to which extent placebo analgesia and nocebo hyperalgesia effects are present in patients experiencing mild-to-moderate AD. Twenty-one patients with AD (test population) and 26 healthy participants (HP; design validation) were exposed to thermal pain stimulation on 3 test days: Lidocaine condition (open/hidden lidocaine administration), capsaicin condition (open/hidden capsaicin administration), and natural history (no treatment), in a randomized, within-subject design. Open lidocaine and open capsaicin were accompanied by verbal suggestions for pain relief and pain increase, respectively. Expected pain and actual pain intensity were measured on a numerical rating scale (0-10). Placebo and nocebo effects were calculated as pain differences in open-hidden lidocaine and capsaicin, respectively, controlled for no treatment. Healthy participants obtained a placebo effect ( P = 0.01) and a trend for a nocebo effect ( P = 0.07). Patients with AD did not obtain a placebo effect ( P = 0.44) nor a significant nocebo effect ( P = 0.86). Healthy participants expected lower and higher pain with open vs hidden lidocaine and capsaicin, respectively ( P < 0.001). The same expectation effects were seen in patients with AD (open vs hidden lidocaine, P = 0.008; open vs hidden capsaicin, P < 0.001). With a well-controlled experimental setting, this study suggests that patients with AD may not experience placebo analgesia effects. Nocebo hyperalgesia effects in patients with AD needs further research. These findings may have implications for the conduction of clinical trials and the treatment of patients with AD in clinical practice.

Historical evolution of the scientific investigation of the placebo analgesic effect.

Historical evolution of the scientific investigation of the placebo analgesic effect.

Personality differences in brain network mechanisms for placebo analgesia and nocebo hyperalgesia in experimental pain: a functional magnetic resonance imaging study.

BackgroundPlacebo and nocebo responses have been increasingly gaining the attention of clinical and scientific researchers. Inconsistent conclusions from current studies indicate that different factors potentially affect both placebo and nocebo responses. Increasing evidence suggests that personality differences may affect the mechanisms of both two responses. In the present work, we explored the characteristics of neural signals of placebo and nocebo responses based on functional connectivity (FC) analysis and Granger causality analysis (GCA).MethodsA total of 34 healthy participants received conditional induction training to establish placebo and nocebo responses. Every participant completed the following experimental workflow, including scanning of baseline, experimental low back pain model establishment, scanning of acute pain status, and scanning of placebo response or nocebo response. We collect visual analogue scale (VAS) data after each scanning. Functional magnetic resonance imaging (fMRI) data from different personality groups were subjected to FC analysis and multivariate GCA (mGCA).ResultsPain scores for placebo and nocebo responses were statistically different across different personality. There are also statistically differences in the neural signals of two responses across different personality.ConclusionsThe findings of the present study indicated that extroverted and introverted participants are likely to experience placebo analgesic effects and nocebo hyperalgesia effects, respectively. Both extroverted and introverted participants showed significant changes in brain networks under placebo response. Variation in emotional control and ventromedial prefrontal cortex inactivity may constitute the bulk of the personality differences in placebo analgesia. Differences in the regulation of the sensory conduction system (SCS) and release of the emotional circuit could be important factors affecting personality differences in nocebo hyperalgesia.

Personality Differences of Brain Networks in Placebo Analgesia and Nocebo Hyperalgesia: A Psychophysiological Interaction (PPI) Approach in fMRI.

It is generally believed that the placebo response can elicit an analgesic effect, whilst the nocebo response can elicit a hyperalgesia effect in pain. Placebo analgesia and nocebo hyperalgesia effects are increasing concerns for researchers. Growing evidence suggests personality differences have an impact on both placebo and nocebo effects. However, previous studies have not reached a unified conclusion. We designed this study to explore the personality differences of functional magnetic resonance imaging (fMRI) signals in placebo response and nocebo response by using psychophysiological interaction (PPI) analysis. 30 healthy subjects underwent conditioning induction training to establish expectations of placebo effect and nocebo effect, and then, all subjects completed the following experimental procedures: (1) baseline scanning, (2) acute pain model establishment, (3) pain status scanning, and (4) pseudorandom scanning of block design of placebo response or nocebo response. Behavioral data were collected after each scan. The results of this study showed that (1) there were significant differences of VAS placebo intervention between the extrovert group and the introvert group (p = 0.004); (2) there were significant differences of VAS nocebo intervention between the extrovert group and the introvert group (p = 0.011); (3) there were significant differences between the VAS placebo intervention and VAS pain status (baseline) in both the extrovert group (p < 0.001) and the introvert group (p = 0.001); (4) there were significant differences between the VAS nocebo intervention and VAS pain status (baseline) in both the extrovert group (p = 0.008) and the introvert group (p < 0.001). Moreover, there were significant differences in the brain network for placebo and nocebo responses between different personalities. We found that (1) deactivation differences of the pain-related network and limbic system play an important role in personality differences associated with placebo analgesia and (2) differences of control of anxiety and activation of dorsolateral prefrontal cortex may cause the personality differences observed in nocebo hyperalgesia.

Another's pain in my brain: No evidence that placebo analgesia affects the sensory-discriminative component in empathy for pain

The shared representations account of empathy suggests that sharing other people's emotions relies on neural processes similar to those engaged when directly experiencing such emotions. Recent research corroborated this by showing that placebo analgesia induced for first-hand pain resulted in reduced pain empathy and decreased activation in shared neural networks. However, those studies did not report any placebo-related variation of somatosensory engagement during pain empathy. The experimental paradigms used in these studies did not direct attention towards a specific body part in pain, which may explain the absence of effects for somatosensation. The main objective of this preregistered study was to implement a paradigm overcoming this limitation, and to investigate whether placebo analgesia may also modulate the sensory-discriminative component of empathy for pain. We induced a localized, first-hand placebo analgesia effect in the right hand of 45 participants by means of a placebo gel and conditioning techniques, and compared this to the left hand as a control condition. Participants underwent a pain task in the MRI scanner, receiving painful or non-painful electrical stimulation on their left or right hand, or witnessing another person receiving such stimulation. In contrast to a robust localized placebo analgesia effect for self-experienced pain, the empathy condition showed no differences between the two hands, neither for behavioral nor neural responses. We thus report no evidence for somatosensory sharing in empathy, while replicating previous studies showing overlapping brain activity in the affective-motivational component for first-hand and empathy for pain. Hence, in a more rigorous test aiming to overcome limitations of previous work, we again find no causal evidence for the engagement of somatosensory sharing in empathy. Our study refines the understanding of the neural underpinnings of empathy for pain, and the use of placebo analgesia in investigating such models.

Modeling Learning Patterns to Predict Placebo Analgesic Effects in Healthy and Chronic Orofacial Pain Participants.

Successfully predicting the susceptibility of individuals to placebo analgesics will aid in developing more effective pain medication and therapies, as well as aiding potential future clinical use of placebos. In pursuit of this goal, we analyzed healthy and chronic pain patients' patterns of responsiveness during conditioning rounds and their links to conditioned placebo analgesia and the mediating effect of expectation on those responses. We recruited 579 participants (380 healthy, 199 with temporomandibular disorder [TMD]) to participate in a laboratory placebo experiment. Individual pain sensitivity dictated the temperatures used for high- and low-pain stimuli, paired with red or green screens, respectively, and participants were told there would be an analgesic intervention paired with the green screens. Over two conditioning sessions and one testing session, participants rated the painfulness of each stimulus on a visual analogue scale from 0 to 100. During the testing phase, the same temperature was used for both red and green screens to assess responses to the placebo effect, which was defined as the difference between the average of the high-pain-cue stimuli and low-pain-cue stimuli. Delta scores, defined as each low-pain rating subtracted from its corresponding high-pain rating, served as a means of modeling patterns of conditioning strength and placebo responsiveness. Latent class analysis (LCA) was then conducted to classify the participants based on the trajectories of the delta values during the conditioning rounds. Classes characterized by persistently greater or increasing delta scores during conditioning displayed greater placebo analgesia during testing than those with persistently lower or decreasing delta scores. Furthermore, the identified groups' expectation of pain relief acted as a mediator for individual placebo analgesic effects. This study is the first to use LCA to discern the relationship between patterns of learning and the resultant placebo analgesia in chronic pain patients. In clinical settings, this knowledge can be used to enhance clinical pain outcomes, as chronic pain patients with greater prior experiences of pain reduction may benefit more from placebo analgesia.

The Context of Values in Pain Control: Understanding the Price Effect in Placebo Analgesia

The experience of pain relief arises from physiological and psychological factors, and attributes such as the commercial features of analgesic treatments have been shown to influence placebo analgesia by affecting treatment expectations. Therefore, treatment valuation from price information should influence the placebo analgesic effect. This hypothesis was tested in a functional magnetic resonance imaging study in which healthy subjects were enrolled in a 2-day experiment. On day 1, the participants (n = 19) had treatment experiences with 2 different placebo creams during a conditioning session without receiving information on treatment price. On day 2, placebo analgesia was tested after providing price information (high vs low) while functional magnetic resonance imaging was performed. The results showed that the higher priced placebo treatment leads to enhanced pain relief. Placebo analgesia in response to the higher priced treatment was associated with activity in the ventral striatum, ventromedial prefrontal cortex, and ventral tegmental area. The behavioral results indicate that the experience of pain was influenced by treatment valuation from price. Our findings reveal that the context of values in pain control is associated with activity in expectation- and reward-related circuitry. PerspectiveTreatment with higher price was associated with enhanced placebo analgesia, and this effect was influenced by activities in expectation and reward processing brain areas. The context of value such as medical cost influences cognitive evaluation processes to modulate pain. Our study may help evaluate a patient's preference toward high-priced drugs.

Are Individual Learning Experiences More Important Than Heritable Tendencies? A Pilot Twin Study on Placebo Analgesia.

Objective: Predicting who will be a placebo responder is a prerequisite to maximize placebo effects in pain treatment and to minimize them in clinical trials. First evidence exists that genetics could affect placebo effects. However, a classical twin study to estimate the relative contribution of genetic influences compared to common and individual environmental influences in explaining interindividual differences in placebo responsiveness has yet not been performed. Methods: In a first explorative twin study, 25 monozygotic (MZ) and 14 dizygotic (DZ) healthy twin pairs (27.5 ± 7.7 years; 73% female) were conditioned to the efficacy of a placebo analgesic ointment with an established heat pain paradigm on their non-dominant arm. Placebo analgesia was then tested on their dominant arm. Furthermore, warmth detection thresholds (WDTs) and heat pain thresholds (HPTs) were assessed, and participants filled in questionnaires for the assessment of psychological traits such as depression, anxiety, optimism, pain catastrophizing, and sensitivity to reward and punishment. Their expectations were determined with a visual analog scale. Results: There was a small but significant placebo analgesic effect in both MZ and DZ twins. Estimates of heritability were moderate for WDT only but negligible for HPT, the conditioning response, and placebo analgesia. Common environment did not explain any variance, and the individual environment explained the largest parts. Therefore, the placebo analgesia response can be seen as influenced by individual learning experiences during the conditioning procedure, whereas other variables assessed were not associated. Conclusions: Compared to the individual learning experience, genetic influences seem to play a minor role in explaining variation in placebo analgesia in this experimental paradigm. However, our results are restricted to placebo effects through conditioning on pain in healthy volunteers and should be replicated in larger samples and in patients. Furthermore, potential gene–environment interactions should be further investigated.

Placebo analgesia effects across central nervous system diseases: what do we know and where do we need to go?

Placebo effects are well established in healthy participants experiencing experimental or acute pain. Yet, little is known about the mechanisms of placebo analgesia effects in patients with chronic pain and even less is known in patients suffering from central nervous system (CNS) diseases where pain is prevalent, difficult to manage, and often undertreated. This article briefly reviews the current knowledge of placebo analgesia effects in healthy participants with the aim of discussing how the mechanisms in placebo analgesia differ between healthy participants and patients. The focus will be on placebo analgesia effects in chronic pain conditions as well as in 2 CNS diseases: Alzheimer disease and Parkinson disease. Finally, strengths and weaknesses of the current knowledge will be discussed and it will be demonstrated how insights from the placebo literature may point to new ways of improving treatments among patients experiencing pain in relation to CNS diseases.

Placebo analgesia

Placebos are drugs, devices, or other treatments that are physically and pharmacologically inert. The placebo effects are therapeutic responses to the context of the treatment process. They are mediated by factors, such as training of a patient, his/her expectations associated with treatment, as well as social conditions, the features of cognitive functioning, etc. and can affect the clinical and physiological responses caused by the health status. The analgesic effects of placebo in different types of pain syndromes reach 25–80%. The formation of placebo analgesia involves the brain structures that belong to the pain matrix and are implicated in the basic processes of perception, in the mechanisms of pain modulation, and in a number of other cognitive and affective processes, as well as in the emotional reactions not caused by pain. A deeper understanding of the mechanisms of action of placebo analgesia can optimize the strategy of current pain therapy.

Failure to Find a Conditioned Placebo Analgesic Response.

Background: Associative learning has, in several studies, been modulated by the sex of the participant. Consistent with this, a recent review found that conditioned nocebo effects are stronger in females than in males.Purpose: It has been suggested that conditioned placebo responses are stronger in females, and this hypothesis was investigated in the present study. Cortisol and measures of negative emotions were taken to investigate if these processes could mediate any conditioned placebo effects.Methods: Cold pain was applied to the volar forearm. The Conditioned group received inert capsules prior to two presentations of less painful stimulations, to associate intake of the capsules with reduced pain. The pain control group received the same painful stimulation as the Conditioned group, but no capsules. The Capsule control group received the capsules in the same way as the Conditioned group, but no decrease in the painful stimulation. Participant sex was crossed across groups. It was hypothesized that in the Conditioned group, an expectation of reduced pain should be induced after administration of the capsules, and this should generate placebo analgesia, and mostly so in females.Results: The Conditioned group reported lower pain during conditioning, and rated the capsules as more effective painkillers than the capsule control group. However, placebo analgesia was not reliably observed in the Conditioned group.Conclusion: The placebo capsules were rated as effective painkillers, but this did not translate into a placebo analgesic effect. This could be due to violation of response expectancies, too few conditioning trials, and differences in pain ratings in the pre-test that could be due to previous experience with painkillers.

Phantom Acupuncture Induces Placebo Credibility and Vicarious Sensations: A Parallel fMRI Study of Low Back Pain Patients

Although acupuncture is an effective therapeutic intervention for pain reduction, the exact difference between real and sham acupuncture has not been clearly understood because a somatosensory tactile component is commonly included in the existing sham acupuncture protocols. In an event-related fMRI experiment, we implemented a novel form of sham acupuncture, phantom acupuncture, that reproduces the acupuncture needling procedure without somatosensory tactile stimulation while maintaining the credibility of the acupuncture treatment context. Fifty-six non-specific low back pain patients received either real (REAL) or phantom (PHNT) acupuncture stimulation in a parallel group study. The REAL group exhibited greater activation in the posterior insula and anterior cingulate cortex, reflecting the needling-specific components of acupuncture. We demonstrated that PHNT could be delivered credibly. Interestingly, the PHNT-credible group exhibited bilateral activation in SI/SII and also reported vicarious acupuncture sensations without needling stimulation. The PHNT group showed greater activation in the bilateral dorsolateral/ventrolateral prefrontal cortex (dlPFC/vlPFC). Moreover, the PHNT group exhibited significant pain reduction, with a significant correlation between the subjective fMRI signal in the right dlPFC/vlPFC and a score assessing belief in acupuncture effectiveness. These results support an expectation-related placebo analgesic effect on subjective pain intensity ratings, possibly mediated by right prefrontal cortex activity.

The Placebo Analgesic Effect in Healthy Individuals and Patients: A Meta-Analysis

The present meta-analysis investigates whether the magnitude of placebo analgesia is different in patients compared with healthy individuals and whether placebo analgesia is different in experimentally induced pain compared with clinical pain in patients. A literature search in Web of Science (ISI) on the terms "placebo analgesia" and "placebo analgesic" was conducted. The search resulted in 71 studies, including 4239 participants. Fifty-five studies included healthy individuals and 16 studies included patients. Of the 16 studies with patients, five studies investigated clinical pain and 11 studies investigated experimentally induced pain. The average effect size was 1.24 for healthy individuals and 1.49 for patients. In the studies with patients, the average effect sizes of placebo treatment were 1.73 for experimentally induced pain and 1.05 for clinical pain. A χ test revealed that there were relatively more studies with patients compared with healthy volunteers in which there was a clinically significant reduction in pain (p = .040). The findings suggest that patients benefited from placebo treatment to a greater degree than healthy individuals did and that studies on healthy individuals may underestimate the magnitude of the placebo analgesic effect in patients. Patients' clinical pain and experimentally induced pain respond to placebo to the same degree.

Placebo, nocebo, and neuropathic pain.

Over the last decade, the apparent increase in placebo responses in randomized controlled trials (RCTs) of neuropathic pain have complicated and potentially limited development and availability of new effective pain medication. Placebo analgesia and nocebo hyperalgesia effects are well described in nociceptive and idiopathic pain conditions, but less is known about the magnitude and mechanisms of placebo and nocebo effects in neuropathic pain. In neuropathic pain, placebo treatments have primarily been used as control conditions for active agents under investigation in RCTs and these placebo responses are typically not controlled for the natural history of pain and other confounding factors. Recently, mechanistic studies that control for the natural history of pain have investigated placebo and nocebo effects in neuropathic pain in their own right. Large placebo analgesia but no nocebo hyperalgesic effects have been found, and the underlying mechanisms are beginning to be elucidated. Here we review placebo and nocebo effects and the underlying mechanisms in neuropathic pain and compare them with those of nociceptive and idiopathic pain. This allows for a novel discussion on how knowledge of psychological, neurobiological, and genetic factors underlying well-controlled placebo effects may help improve the information that can be obtained from and potentially restore the utility of RCTs.

Placebo effects in chronic pain conditions. Can placebo components enhance the efficacy of active treatments?

The conceptualization of the placebo phenomenon has changed. Previously placebo was seen as an inactive agent, but today placebo effects are viewed as related to patients’ perception of a treatment. During the last decades, the mechanisms underlying placebo analgesia effects have been specified and it has been shown that patients’ perception of a treatment is influenced by previous experiences, the patient-practitioner relationship as well as expectations and emotions. These factors are, in turn, associated with altered brain activation and release of endogenous opioids, thereby demonstrating that placebo analgesia has a psycho-neurobiological basis. The placebo effect has primarily been investigated in relation to healthy volunteers, but here we review literature on placebo mechanisms in relation to chronic pain states as this is important for an understanding of how placebo factors can be optimized in clinical practice. We outline some of the ethical discussions concerning the use of placebo in clinical practice and we illustrate how patients perception of a treatment contribute to the efficacy of active treatments, thereby showing how focus on patients perception of a treatment may help optimize the outcome of standard active pain treatments in ethically appropriate ways.

The magnitude of placebo analgesia effects depends on how they are conceptualized

ObjectivePlacebo effects are usually calculated as the difference between placebo treatments and no treatments. Recently, placebo-like effects have been investigated using open and hidden administrations of active treatments. The aim of the study was to directly compare the two types of placebo effects and examine how they are influenced by personality traits. MethodsIn a within-subject, randomized, blinded, balanced placebo trial design study with 48 healthy volunteers, we compared placebo and placebo-like effects and tested if expectancy, absorption and suggestibility correlated with these effects. Subjects completed the Tellegen Absorption Scale and the Sensory Suggestibility Scale, and pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections of hypertonic saline with lidocaine or matching placebo in randomized order: open treatment, hidden treatment, placebo and control. The placebo effect was defined as the difference in pain between the placebo and the control condition and the placebo-like effect as the difference in pain between the open and hidden condition. ResultsPlacebo effects were significant both in the traditional paradigm: mean placebo effect AUC 1626mm2 (95% CI 958–2293) and the open–hidden paradigm: mean placebo-like effect AUC 801mm2 (95% CI 134–1469), but there was a significant difference between the magnitude of the two effects (p=0.049). Absorption and suggestibility did not predict the placebo or the placebo-like effect. Estimated expected pain relief correlated with placebo effects but not placebo-like effects. ConclusionThe magnitude of placebo effects differs depending on how they are conceptualized and calculated.

Placebo analgesia: understanding the mechanisms.

Expectations of pain relief drive placebo analgesia. Understanding how expectations of improvement trigger distinct biological systems to shape therapeutic analgesic outcomes has been the focus of recent pharmacologic and neuroimaging studies in the field of pain. Recent findings indicate that placebo effects can imitate the actions of real painkillers and promote the endogenous release of opioids and nonopioids in humans. Social support and observational learning also contribute to placebo analgesic effects. Distinct psychological traits can modulate expectations of analgesia, which facilitate brain pain control mechanisms involved in pain reduction. Many studies have highlighted the importance and clinical relevance of these responses. Gaining deeper understanding of these pain modulatory mechanisms has important implications for personalizing patient pain management.

Molecular mechanisms of placebo responses in humans.

Endogenous opioid and non-opioid mechanisms [e.g. dopamine (DA), endocannabinoids (eCB)] have been implicated in the formation of placebo analgesic effects, with initial reports dating back three-decades. Besides the perspective that placebo effects confound randomized clinical trials (RCTs), the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography (PET) and the selective μ-opioid and D2/3 radiotracers [11C]carfentanil and [11C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (e.g. mood and anxiety disorders, persistent pain syndromes, or even Parkinson Disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.

The expression of cannabinoid receptor 1 is significantly increased in atopic patients

The expression of cannabinoid receptor 1 is significantly increased in atopic patients

Enhancing the Placebo Response: Functional Magnetic Resonance Imaging Evidence of Memory and Semantic Processing in Placebo Analgesia

Two groups of patients with irritable bowel syndrome rated pain and underwent functional magnetic resonance imaging brain scanning during experimentally induced rectal distension (20 seconds, 7 stimuli). Group 1 was tested under baseline (natural history [NH]) and a verbally induced placebo condition, whereas Group 2 was tested under baseline and standard placebo (no verbal suggestion for pain reduction) and intrarectal lidocaine conditions. As hypothesized, intrarectal lidocaine reduced evoked pain and pain-related brain activity within Group 2. Between-group comparisons showed that adding a verbal suggestion to a placebo condition increased neural activity involved in memory and semantic processing, areas that process the placebo suggestions. These areas, in turn, are likely to influence brain areas involved in emotions and analgesia and consequently the placebo effect. These placebo suggestions also added significant decreases in activity of brain areas that process pain. The test stimulus itself seems to cue these effects and is consistent with previous explanations that somatic focus and sensory feedback reinforce expectations and other factors that mediate placebo analgesic effects. PerspectiveExpectations for pain can be verbally manipulated to produce placebo analgesia. Placebo analgesia is accompanied by decreased brain activity related to processing pain and increased brain activity that generates placebo analgesia, including semantic and memory regions. Placebo suggestions may enhance placebo analgesia by engaging a feedback mechanism triggered by the painful stimulus itself and related to brain mechanisms involved in memory and semantic processing.