Placebo Analgesia Research Articles

Temporal expectancy induced by the mere possession of a placebo analgesic affects placebo analgesia: preliminary findings from a randomized controlled trial

Research on placebo analgesia usually shows that people experienced a reduction in pain after using a placebo analgesic. An emerging line of research argues that, under some circumstances, merely possessing (but not using) a placebo analgesic could induce placebo analgesia. The current study investigates how temporary expectation of pain reduction associated with different forms of possessing a placebo analgesic affects pain outcomes. Healthy participants (n = 90) were presented with a vial of olive oil (placebo), described as a blended essential oil that blocks pain sensations upon nasal inhalation, and were asked to anticipate the benefits of such analgesic oil to the self (such as anticipating the analgesic oil to reduce their pain). Participants were randomized into one of three different possession conditions: physical-possession condition (participants possessed a tangible placebo analgesic oil, inducing an expectation to acquire analgesic benefit early upon the experience of pain), psychological-possession condition (participants possessed a coupon, which can be redeemed for a placebo analgesic oil, inducing an expectation to acquire analgesic benefit later upon the experience of pain), or no-possession condition. Participants did a cold pressor test (CPT) to experience experimentally-induced pain on their non-dominant hand. Their objective physical pain responses (pain-threshold and pain-tolerance), and subjective psychological pain perception (pain intensity, severity, quality, and unpleasantness) were measured. Results revealed that participants in the physical-possession condition reported greater pain-threshold, F(2, 85) = 6.65, p = 0.002, and longer pain-tolerance, F(2, 85) = 7.19, p = 0.001 than participants in the psychological-possession and no-possession conditions. No significant group difference was found in subjective pain perception. The results of this study can advance knowledge about pain mechanisms and novel pain management.

Placebo and hypnosis in the clinical setting: Contextual factors in hypnotic analgesia

ABSTRACT The assumption that hypnotic analgesia produces placebo effects is controversial. The cognitive dimension that can distinguish hypnosis from placebo analgesia has been suggested as hypnotic susceptibility. The aim of this study is to investigate the role of the relationship between patient and therapist, assumed to produce the placebo effect, in the clinical context of hypnotic treatment for pain. Seventy subjects were given hypnosis administered by the therapist in person (Group A) and 37 practiced self-hypnosis (Group B) for 8 weeks. The Somatosensory Amplification Scale (SSAS), Stanford hypnotic susceptibility scale type A, Cold pressor test (CPT) and SCL-90 were administered at baseline, and Italian Pain Questionnaire (IPQ) dimensions were used as outcome measures. The SSAS did appear to reflect the efficacy of hypnotic analgesia in all pain variables explored, but only in Group B. An improvement in pain intensity and all IPQ dimensions were found at 8 weeks. In particular, an improvement in the affective dimension of pain, with a medium–high effect size (η2 = .774), was recorded after hypnotic analgesia, with the outcome being better in Group A than in Group B (p = .001). This outcome was independent of hypnotic susceptibility in both groups. Considering our hypothesis that, given the administration of the same suggestions, the therapist could promote the placebo response, contributing to the improvement in the affective dimension of pain outcome, which exhibited a response to the hypnotic treatment independently of hypnotic susceptibility.

Endogenous opioid system in the medial prefrontal cortex is involved in placebo analgesia

Endogenous opioid system in the medial prefrontal cortex is involved in placebo analgesia

Learning Pain in Context: Response-Conditioned Placebo Analgesia and Nocebo Hyperalgesia in Male Rats with Chronic Neuropathic Pain

Learning Pain in Context: Response-Conditioned Placebo Analgesia and Nocebo Hyperalgesia in Male Rats with Chronic Neuropathic Pain

Observing treatment outcomes in other patients can elicit augmented placebo effects on pain treatment: a double-blinded randomized clinical trial with patients with chronic low back pain.

Clinical research on social observational learning (SoL) as an underlying mechanism for inducing expectancy and eliciting analgesic placebo effects is lacking. This double-blinded randomized controlled clinical trial investigated the influence of SoL on medication-augmenting placebo effects in 44 patients with chronic low back pain. Our hypothesis was that observing positive drug effects on pain and mobility in another patient could increase pain reduction and functional capacity. To test this, we compared the effects of observing positive treatment outcomes in a sham patient (the social learning group [SoLG]) vs hearing the same sham patient report neutral effects (the control group). In the SoLG, the sham patient told peers about pain reduction due to amitriptyline and demonstrated his improved mobility by bending forwards and sideways while he told the control group only that he was taking amitriptyline. The primary outcome was a reduction in clinical low back pain self-ratings. The secondary outcome was perceptions of pain-related disability. The exploratory outcome was mood and coping statements. Data collection occurred before and after the intervention and 2 weeks later. After the intervention, pain decreased in both groups (F [1, 41] = 7.16, P < 0.05, d = 0.83), with no difference between groups. However, the SoLG showed a significantly larger decrease in perceived disability (F [1, 41] = 5, P < 0.05, d = 0.63). The direct observation of patient with chronic low back pain of positive treatment outcomes in the sham patient seems to have enhanced the treatment effects while indirect verbal reports of reduced pain did not.

Real Bodies Not Required? Placebo Analgesia and Pain Perception in Immersive Virtual and Augmented Reality

Pain represents an embodied experience, wherein inferences are not only drawn from external sensory inputs, but also from bodily states. Previous research has demonstrated that a placebo administered to an embodied rubber hand can effectively induce analgesia, providing first evidence that placebos can work even when applied to temporarily embodied, artificial body parts. Using a heat pain paradigm, the present study investigates placebo analgesia and pain perception during virtual embodiment. We examined whether a virtual placebo (a sham heat protective glove) can successfully induce analgesia, even when administered to a virtual body. The analgesic efficacy of the virtual placebo to the real hand (augmented reality setting) or virtual hand (virtual reality setting) was compared to a physical placebo administered to the own, physical body (physical reality setting). Furthermore, pain perception and subjective embodiment were compared between settings. In this mixed design experiment, healthy participants (n = 48) were assigned to either an analgesia-expectation or control-expectation group, where subjective and objective pain was measured at pre- and post-intervention time points. Results demonstrate that pre-intervention pain intensity was lower in the virtual reality setting, and that participants in the analgesia-expectation group, after the intervention, exhibited significantly higher pain thresholds, and lower pain intensity and unpleasantness ratings than control-expectation participants, independent of the setting. Our findings show that a virtual placebo can elicit placebo analgesia comparable to that of a physical placebo, and that administration of a placebo does not necessitate physical bodily interaction to produce analgesic responses. PerspectiveThis study demonstrates that a virtual placebo treatment, even when administered to a virtual body, can produce placebo analgesia. These findings indicate that the efficacy of a virtual placebo is comparable to that of a physical placebo, which could pave the way for effective new non-pharmacological approaches for pain management.

Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial.

Introduction: Open-label placebos have been proposed as way of using long recognized analgesic placebo effects in an ethical manner. Recent evidence shows efficacy of open-label placebos for clinical conditions, but there is need for more research on open-label placebos in acute pain. In the treatment of acute postoperative pain, minimization of opioid related side effects remains one of the key challenges. Therefore, this study aims at investigating the potential of adding unconditioned open-label placebos to treatment as usual as a means of reducing opioid consumption and its related side effects in patients with acute postoperative pain.Methods and Analysis: This is the protocol of an ongoing single site randomized controlled trial. The first patient was enrolled in May 2020. In total, 70 patients suffering from acute postoperative pain following dorsal lumbar interbody fusion are randomized to either a treatment as usual group or an experimental intervention group. The treatment as usual group consists of participants receiving a patient-controlled morphine pump. On day 1 and 2 post-surgery, patients in the intervention group receive, in addition to treatment as usual, two open-label placebo injections per day along with an evidence-based treatment rationale explaining the mechanisms of placebos. The primary outcome is measured by means of self-administered morphine during day 1 and 2 post-surgery. Several other outcome measures including pain intensity and adverse events as well as potential predictors of placebo response are assessed. Analysis of covariance will be used to answer the primary research question and additional statistical techniques such as generalized linear mixed models will be applied to model the temporal course of morphine consumption.Discussion: This study will provide valuable insights into the efficacy of open-label placebos in acute pain and will potentially constitute an important step toward the implementation of open-label placebos in the clinical management of acute postoperative pain. In addition, it will shed light on a cost-efficient and patient-centered strategy to reduce opioid consumption and its related side effects, without any loss in pain management efficacy.Ethics and Dissemination: The “Ethikkommission Nordwest- und Zentralschweiz” (BASEC2020-00099) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal.Clinical Trial Registration: The study is registered at ClinicalTrials.gov (NCT04339023) and is listed in the Swiss national registry at kofam.ch (SNCTP000003720).

A social affective neuroscience lens on placebo analgesia.

Pain is a fundamental experience that promotes survival. In humans, pain stands at the intersection of multiple health crises: chronic pain, the opioid epidemic, and health disparities. The study of placebo analgesia highlights how social, cognitive, and affective processes can directly shape pain, and identifies potential paths for mitigating these crises. This review examines recent progress in the study of placebo analgesia through affective science. It focuses on how placebo effects are shaped by expectations, affect, and the social context surrounding treatment, and discusses neurobiological mechanisms of placebo, highlighting unanswered questions and implications for health. Collaborations between clinicians and social and affective scientists can address outstanding questions and leverage placebo to reduce pain and improve human health.

Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission

Behavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain μ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed 37 healthy human volunteers to a standardized pain challenge on each of 2 days within a Positron Emission Tomography (PET) neuroimaging paradigm using the MOR selective radiotracer, 11C-Carfentanil (CFN). Each day volunteers received an intervention (placebo under analgesic expectation or no treatment), completed PET scanning, and rated their pain experience. MOR BPND parametric maps were generated from PET scans using standard methods. Results showed placebo reduced plasma IL-18 during pain (W74 = −3.7, p < 0.001), the extent correlating with reduction in pain scores. Placebo reduction in IL-18 covaried with placebo-induced endogenous opioid release in the left nucleus accumbens (T148 = 3.33; puncorr < 0.001) and left amygdala (T148 = 3.30; puncorr < 0.001). These findings are consistent with a modulating effect of placebo (under analgesic expectation in humans) on a potent nociceptive, pro-inflammatory cytokine (IL-18) and underlying relationships with endogenous opioid activity, a neurotransmitter system critically involved in pain, stress, and mood regulation.

The effect of treatment expectations on pruritus and skin pain

HintergrundPatientenerwartungen in Bezug auf den Nutzen einer medizinischen Behandlung stellen eine wichtige Determinante für die Placeboantwort dar. Sie können Entwicklung und Verlauf von Erkrankungen sowie Wirksamkeit und Verträglichkeit von Therapien maßgeblich beeinflussen. Die Mechanismen, die diese Placebo- und Noceboeffekte vermitteln, wurden bislang am besten auf dem Gebiet der Placeboanalgesie beschrieben. Aber auch in der Dermatologie findet sich eine zunehmende Evidenz dafür, dass verschiedene Symptome wie Schmerzen an der Haut und Pruritus (Jucken) sowie verschiedene dermatologische Erkrankungen durch die Behandlungserwartungen von Patienten moduliert werden können.Ziel der ArbeitDas Ziel dieser Arbeit ist die Darstellung der aktuellen Datenlage in Bezug auf den Einfluss von Erwartungseffekten auf dermatologische Symptome wie Pruritus und Hautschmerzen sowie auf verschiedene dermatologische Erkrankungen. Schließlich soll die Bedeutung dieses Themas für Ärzte, die Patienten mit Hautsymptomen behandeln, vermittelt werden.Material und MethodenEs handelt sich um eine narrative Übersichtsarbeit.Ergebnisse und DiskussionEine zunehmende Anzahl von Studien an gesunden Probanden und dermatologischen Patienten zeigt, dass Hautsymptome wie Pruritus und Schmerzen durch die Induktion positiver Erwartungen verringert und durch die Induktion negativer Erwartungen verstärkt werden können. Vorherige Behandlungserfahrungen der Patienten sowie die Qualität und Quantität der Arzt-Patienten-Kommunikation spielen für die Induktion der Behandlungserwartung eine zentrale Rolle.SchlussfolgerungTechniken, die darauf abzielen, positive Erwartungseffekte von Patienten mit Hautsymptomen zu maximieren und negative zu minimieren, sollten in die klinische Routine implementiert werden.

Brainstem Mechanisms of Pain Modulation: A within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses.

Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N = 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn.SIGNIFICANCE STATEMENT Understanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.

The Effect of the Model's Social Status on Placebo Analgesia Induced by Social Observational Learning.

BackgroundPlacebo analgesia can be induced by social observational learning. The aim of this study was to determine whether this effect can be influenced by the social status of a model.MethodsHealthy volunteers were randomly assigned to three groups: a group that observed a video featuring a high-status model (introduced as a professor), a group that observed a video featuring a low-status model (introduced as a janitor), and a control group. Participants observed videos showing a model (of high or low status) undergoing the experimental procedure, during which he received pain stimuli. In each group, half of participants watched a video in which the model rated blue stimuli as more painful (6–8 on the numeric rating scale) and orange stimuli as less painful (1–3 on the numeric rating scale), whereas the other half of participants watched a video in which the model rated orange stimuli as more painful and blue stimuli as less painful. Participants in the control group did not watch any video. Then, all participants received 16 electrocutaneous pain stimuli of the same intensity, preceded by either blue or orange colors. The perceived social status of the model and the trait empathy of participants were measured.ResultsPlacebo analgesia was induced in both experimental groups, yet no difference in the magnitude of the effect was found. However, we found that the participants’ individual ratings of the model’s social status predicted the magnitude of placebo analgesia.ConclusionThis is the first study to show that the perception of a model’s social status is related to the magnitude of placebo analgesia induced by observational learning.

Cutoff criteria for the placebo response: a cluster and machine learning analysis of placebo analgesia

Computations of placebo effects are essential in randomized controlled trials (RCTs) for separating the specific effects of treatments from unspecific effects associated with the therapeutic intervention. Thus, the identification of placebo responders is important for testing the efficacy of treatments and drugs. The present study uses data from an experimental study on placebo analgesia to suggest a statistical procedure to separate placebo responders from nonresponders and suggests cutoff values for when responses to placebo treatment are large enough to be separated from reported symptom changes in a no-treatment condition. Unsupervised cluster analysis was used to classify responders and nonresponders, and logistic regression implemented in machine learning was used to obtain cutoff values for placebo analgesic responses. The results showed that placebo responders can be statistically separated from nonresponders by cluster analysis and machine learning classification, and this procedure is potentially useful in other fields for the identification of responders to a treatment.

ERP Indicators of Self-Pain and Other Pain Reductions due to Placebo Analgesia Responding: The Moderating Role of the Fight-Flight-Freeze System.

This study evaluates the modulation of phasic pain and empathy for pain induced by placebo analgesia during pain and empathy for pain tasks. Because pain can be conceptualized as a dangerous stimulus that generates avoidance, we evaluated how approach and avoidance personality traits modulate pain and empathy for pain responses. We induced placebo analgesia to test whether this also reduces self-pain and other pain. Amplitude measures of the N1, P2, and P3 ERPs components, elicited by electric stimulations, were obtained during a painful control, as well as during a placebo treatment expected to induce placebo analgesia. The placebo treatment produced a reduction in pain and unpleasantness perceived, whereas we observed a decrease in the empathy unpleasantness alone during the empathy pain condition. The moderator effects of the fight-flight-freeze system (FFFS) in the relationships linking P2 and P3 amplitude changes with pain reduction were both significant among low to moderate FFFS values. These observations are consistent with the idea that lower FFFS (active avoidance) scores can predict placebo-induced pain reduction. Finally, in line with the revised Reinforcement Sensitivity Theory (r-RST), we can assume that phasic pain is an aversive stimulus activating the active-avoidance behavior to bring the system back to homeostasis.

Brain Network to Placebo and Nocebo Responses in Acute Experimental Lower Back Pain: A Multivariate Granger Causality Analysis of fMRI Data.

Background and Objective: Placebo and nocebo responses are widely observed. Herein, we investigated the nocebo hyperalgesia and placebo analgesia responses in brain network in acute lower back pain (ALBP) model using multivariate Granger causality analysis (GCA). This approach analyses functional magnetic resonance imaging (fMRI) data for lagged-temporal correlation between different brain areas.Method: After completing the ALBP model, 20 healthy subjects were given two interventions, once during a placebo intervention and once during a nocebo intervention, pseudo-randomly ordered. fMRI scans were performed synchronously during each intervention, and visual analog scale (VAS) scores were collected at the end of each intervention. The fMRI data were then analyzed using multivariate GCA.Results: Our results found statistically significant differences in VAS scores from baseline (pain status) for both placebo and nocebo interventions, as well as between placebo and nocebo interventions. In placebo network, we found a negative lagged-temporal correlation between multiple brain areas, including the dorsolateral prefrontal cortex (DLPFC), secondary somatosensory cortex area, anterior cingulate cortex (ACC), and insular cortex (IC); and a positive lagged-temporal correlation between multiple brain areas, including IC, thalamus, ACC, as well as the supplementary motor area (SMA). In the nocebo network, we also found a positive lagged-temporal correlation between multiple brain areas, including the primary somatosensory cortex area, caudate, DLPFC and SMA.Conclusion: The results of this study suggest that both pain-related network and reward system are involved in placebo and nocebo responses. The placebo response mainly works by activating the reward system and inhibiting pain-related network, while the nocebo response is the opposite. Placebo network also involves the activation of opioid-mediated analgesia system (OMAS) and emotion pathway, while nocebo network involves the deactivation of emotional control. At the same time, through the construction of the GC network, we verified our hypothesis that nocebo and placebo networks share part of the same brain regions, but the two networks also have their own unique structural features.

Influences of EEG Activity, HRV, and Personality Traits on Placebo Analgesia During Self-Pain and Empathy for Pain

Influences of EEG Activity, HRV, and Personality Traits on Placebo Analgesia During Self-Pain and Empathy for Pain

Influences of EEG Alpha2 Power Changes and Hypnotic Suggestibility on Placebo Analgesia: The Mediation Role of Involuntariness

Influences of EEG Alpha2 Power Changes and Hypnotic Suggestibility on Placebo Analgesia: The Mediation Role of Involuntariness

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Brainstem Pain-Modulation Circuitry and Its Plasticity in Neuropathic Pain: Insights From Human Brain Imaging Investigations.

Acute pain serves as a protective mechanism that alerts us to potential tissue damage and drives a behavioural response that removes us from danger. The neural circuitry critical for mounting this behavioural response is situated within the brainstem and is also crucial for producing analgesic and hyperalgesic responses. In particular, the periaqueductal grey, rostral ventromedial medulla, locus coeruleus and subnucleus reticularis dorsalis are important structures that directly or indirectly modulate nociceptive transmission at the primary nociceptive synapse. Substantial evidence from experimental animal studies suggests that plasticity within this system contributes to the initiation and/or maintenance of chronic neuropathic pain, and may even predispose individuals to developing chronic pain. Indeed, overwhelming evidence indicates that plasticity within this circuitry favours pro-nociception at the primary synapse in neuropathic pain conditions, a process that ultimately contributes to a hyperalgesic state. Although experimental animal investigations have been crucial in our understanding of the anatomy and function of the brainstem pain-modulation circuitry, it is vital to understand this system in acute and chronic pain states in humans so that more effective treatments can be developed. Recent functional MRI studies have identified a key role of this system during various analgesic and hyperalgesic responses including placebo analgesia, offset analgesia, attentional analgesia, conditioned pain modulation, central sensitisation and temporal summation. Moreover, recent MRI investigations have begun to explore brainstem pain-modulation circuitry plasticity in chronic neuropathic pain conditions and have identified altered grey matter volumes and functioning throughout the circuitry. Considering the findings from animal investigations, it is likely that these changes reflect a shift towards pro-nociception that ultimately contributes to the maintenance of neuropathic pain. The purpose of this review is to provide an overview of the human brain imaging investigations that have improved our understanding of the pain-modulation system in acute pain states and in neuropathic conditions. Our interpretation of the findings from these studies is often guided by the existing body of experimental animal literature, in addition to evidence from psychophysical investigations. Overall, understanding the plasticity of this system in human neuropathic pain conditions alongside the existing experimental animal literature will ultimately improve treatment options.

Escalating morphine dosage fails to elicit conditioned analgesia in a preclinical chronic neuropathic pain model.

Many people with chronic pain escalate their opioid dosage to counteract tolerance effects. A treatment regimen consisting of placebos admixed with opioids has been suggested as a possible therapeutic option that could reduce the harm of long-term opioid use. However, the analgesic efficacy of such a regimen requires further investigation before widespread adoption. We have recently reported that a 4-day pharmacological conditioning procedure, which paired morphine (6 mg/kg) with contextual cues, elicited placebo analgesia in subpopulations of male (35%) and female (25%) rats with sciatic nerve chronic constriction injury (CCI). Here, we investigated how an escalating morphine dosage during conditioning affects the incidence and strength of placebo analgesia. Forty-four male, Sprague-Dawley rats received CCI. Thirty-eight (86%) rats developed strong cold allodynia by day 6 post-surgery, as measured by hind paw withdrawal (HPW) behaviour on a 5°C cold plate (120 s). In this experiment, pharmacological conditioning consisted of an escalating morphine dose over 4 days (8/9/10/12 mg/kg). This dosing regimen produced strong reductions in HPW behaviour and counteracted the effects of morphine tolerance during conditioning. However, none of the rats given the placebo treatment (n = 12) demonstrated reductions in HPW behaviour when morphine was substituted for saline (i.e. placebo analgesia), but instead showed a strong behavioural response (rearing). These results demonstrate that a high, escalating dose of morphine failed to produce conditioned placebo analgesia in rats with CCI. It is possible that admixing placebos with opioids may be similarly ineffective in chronic pain patients when the opioids regimen is high or escalating.