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Pain Jun 2020Classical conditioning and expectations are well-known underlying mechanisms of placebo hypoalgesia. Only little is known about their differential effect in adults,...
Classical conditioning and expectations are well-known underlying mechanisms of placebo hypoalgesia. Only little is known about their differential effect in adults, however, and even less in children. Previous studies in children evoked placebo hypoalgesia either with expectations alone or in combination with classical conditioning and revealed conflicting results. Furthermore, these studies investigated children of different ages making it even more difficult to draw conclusions. This study tried to disentangle classical conditioning and expectations by investigating them separately. To examine age effects, n = 172 children (6-9, 10-13, and 14-17 years) as well as n = 32 adults (> = 18 years) were tested using a heat pain paradigm investigating the effectiveness of creams some of which were bogusly introduced as analgesic. In addition to subjective pain intensity ratings, peripheral physiological measures were recorded. Results showed a successful induction of placebo hypoalgesia by both mechanisms for pain ratings and heart rate acceleration. Placebo hypoalgesia was particularly pronounced in children younger than 14 years. Furthermore, placebo hypoalgesia was more marked in children whose mothers raised the expectations. It was also stronger in participants who noticed a strong pain reduction during learning trials. These results encourage the use of placebo effect in clinical practice, particularly for younger children. They underline the relevance of an initial pain reduction and encourage the inclusion of parents in treatment.
Topics: Adolescent; Adult; Child; Humans; Motivation; Pain; Pain Measurement; Pain Perception; Placebo Effect
PubMed: 31977929
DOI: 10.1097/j.pain.0000000000001811 -
Expert Review of Neurotherapeutics Jan 2022The widespread use of the word 'placebo' in the medical literature emphasizes the importance of this phenomenon in modern biomedical sciences. Neuroscientific research...
INTRODUCTION
The widespread use of the word 'placebo' in the medical literature emphasizes the importance of this phenomenon in modern biomedical sciences. Neuroscientific research over the past thirty years shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and can be robust in both laboratory and clinical settings.
AREAS COVERED
Here the authors describe the biological mechanisms and the clinical implications of placebo effects with particular emphasis on neurology and psychiatry, for example in pain, movement disorders, depression. In these conditions, a number of endogenous systems have been identified, such as endogenous opioids, endocannabinoids, and dopamine, which contribute to the placebo-induced benefit.
EXPERT OPINION
Every effort should be made to maximize the placebo effect and reduce its evil twin, the nocebo effect, in medical practice. This does not require the administration of a placebo, but rather the enhancement of the effects of pharmacological and nonpharmacological treatments through a good doctor-patient interaction.
Topics: Humans; Nocebo Effect; Pain; Placebo Effect
PubMed: 34845956
DOI: 10.1080/14737175.2022.2012156 -
Psychosomatic Medicine Jan 2021Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on...
OBJECTIVE
Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on the direction and magnitude of the effect, whereas little is known about the influence of temporal information.
METHODS
Using an experimental placebo and nocebo design, we investigated whether information about the expected onset of a treatment effect modulates the start and time course of analgesic and hyperalgesic responses. Healthy volunteers (n = 166) in three placebo and three nocebo groups were informed that the application of an (inert) cream would reduce (placebo groups) or amplify pain (nocebo groups) after 5, 15, or 30 minutes. Two control groups were also included (natural history and no expectations). Participants' pain intensity rating of electrical stimuli administered before and 10, 20, and 35 minutes after cream application was obtained.
RESULTS
Mixed-method analysis of variance showed a significant interaction between group and time (F(12,262) = 18.172, p < .001, pη2 = 0.454), suggesting that pain variations differed across time points and between groups. Post hoc comparisons revealed that the placebo and nocebo groups began to show a significantly larger change in perceived pain intensity than the no-expectancy control group at the expected time point (p < .05) but not earlier (p > .05). Once triggered, the analgesic effect remained constant over the course of the experiment, whereas the hyperalgesic effect increased over time.
CONCLUSIONS
Our results indicate that temporal suggestions can shape expectancy-related treatment effects, which, if used systematically, could open up new ways to optimize treatment outcome.
Topics: Analgesia; Humans; Hyperalgesia; Nocebo Effect; Pain; Pain Management; Placebo Effect
PubMed: 33109926
DOI: 10.1097/PSY.0000000000000882 -
Supportive Care in Cancer : Official... Nov 2021To investigate the presence of a placebo dose-response effect in four randomized, double-blind, placebo-controlled, multi-dose hot flash clinical trials conducted at... (Meta-Analysis)
Meta-Analysis
PURPOSE
To investigate the presence of a placebo dose-response effect in four randomized, double-blind, placebo-controlled, multi-dose hot flash clinical trials conducted at Mayo Clinic.
METHODS
Hot flash score, frequency, and hot flash-related distress for each placebo dose level were summarized at each time point by mean and standard deviation and changes from baseline were plotted to visualize a possible placebo dose-effect response. Furthermore, a meta-analysis was conducted for each endpoint in the highest and lowest dosage arms across the four trials.
RESULTS
Longitudinal plots of mean hot flash scores, frequencies, and hot flash-related distress scores in patients taking placebo in each study showed a decline in hot flash scores over time without any clinically meaningful differences between the lowest and highest dosage arms in each study. The meta-analysis for each endpoint in the highest and lowest dosage arms across the four trials revealed no clinically important differences either.
CONCLUSION
While the current study cannot rule out the existence of a placebo dose-response effect in multi-dose placebo-controlled trials in patients with hot flashes or other conditions, it suggests, along with the available data in the placebo literature, that, at least in well-conducted multi-dose clinical trials in which the placebo was used as control, such an effect, if it exists at all, should be very small. Therefore, pooling data from different placebo subgroups is unlikely to compromise the validity of comparisons between the combined placebo arms and each treatment arm.
Topics: Double-Blind Method; Hot Flashes; Humans; Placebo Effect; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 33973082
DOI: 10.1007/s00520-021-06244-3 -
Otology & Neurotology : Official... Apr 2024To quantify the placebo effect in randomized clinical trials treating tinnitus with oral or intratympanic placebo treatment. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To quantify the placebo effect in randomized clinical trials treating tinnitus with oral or intratympanic placebo treatment.
DATA SOURCES
CINAHL, PubMed, and Scopus were searched for articles from conception to October 2022. MESH and key terms such as "tinnitus," "placebo," and "medication" were used to find randomized, placebo-controlled trials. The search was limited to articles in English.
METHODS
Randomized controlled trials with adult subjects evaluating tinnitus pretreatment and posttreatment with an oral or intratympanic medication versus a placebo arm were included. Crossover studies, studies involving middle/inner ear operations or devices, and studies that exclusively included nonidiopathic etiologies of tinnitus were excluded. Mean tinnitus symptom survey scores for the Tinnitus Handicap Inventory (THI), Tinnitus Severity Index, Tinnitus Functional Index, Tinnitus Handicap Questionnaire, and Visual Analog Scales for tinnitus Intensity/Loudness (VAS-L), Annoyance (VAS-An), and Awareness (VAS-Aw) were extracted for both placebo and experimental groups.
RESULTS
953 studies were screened with 23 studies being included in the final analysis. Meta-analysis of mean difference (MD) was calculated using RevMan 5.4. MD between pretreatment and posttreatment THI scores of the placebo arms was 5.6 (95% confidence interval, 3.3-8.0; p < 0.001). MD between pretreatment and posttreatment VAS scores of the placebo groups for Loudness, Annoyance, and Awareness were 0.8 (0.0 to 1.6, p = 0.05), 0.2 (-0.2 to 0.5, p = 0.34), and 0.3 (-0.0 to 0.7, p = 0.08), respectively.
CONCLUSIONS
Placebo treatment has shown effectiveness in improving patient-reported evaluations of tinnitus when using some standardized metrics such as THI and VAS-L; however, the improvement is not as substantial as nonplacebo treatment.
Topics: Adult; Humans; Tinnitus; Placebo Effect; Randomized Controlled Trials as Topic; Surveys and Questionnaires
PubMed: 38361332
DOI: 10.1097/MAO.0000000000004139 -
Schmerz (Berlin, Germany) Jun 2022Preoperative treatment expectations have a significant influence on postoperative pain and treatment outcomes. Positive expectations are an important mechanism of the... (Review)
Review
BACKGROUND
Preoperative treatment expectations have a significant influence on postoperative pain and treatment outcomes. Positive expectations are an important mechanism of the placebo effect and negative expectations are an important mechanism of the nocebo effect.
OBJECTIVES
What is the influence of treatment expectations, how are they assessed in the clinical setting, and how can the findings be implemented in clinical practice?
METHODS
A literature search was performed using the keywords "expectation" AND ("postoperative" OR "surgery"). All English and German articles were selected. In addition, the bibliographies of the articles found were examined and incorporated.
RESULTS
A total of 158 articles were found, 49 of which investigate expectations and include postoperative treatment outcomes. Most articles investigate expectations only at baseline to ensure that groups do not differ preoperatively. The studies that prospectively examine the influence of expectations apply very different measurement methods to investigate expectancy constructs. Thus, comparison across studies is difficult. There are few studies examining whether and how expectations can be influenced perioperatively, and who developed practice-relevant interventions to change them.
CONCLUSION
Valid and reliable measurement tools should be applied in clinical trials for a more robust investigation of treatment expectations. Further studies should address possible intervention options so that treatment expectations can also be incorporated into standard clinical care.
Topics: Humans; Motivation; Pain, Postoperative; Placebo Effect; Treatment Outcome
PubMed: 34459995
DOI: 10.1007/s00482-021-00575-0 -
Annals of Behavioral Medicine : a... Jan 2020Choice has been found to facilitate placebo effects for single-session treatments where standard placebo treatment without choice failed to elicit a placebo effect.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Choice has been found to facilitate placebo effects for single-session treatments where standard placebo treatment without choice failed to elicit a placebo effect. However, it is unknown whether choice can enhance the placebo effect for treatments occurring over a period of days and where placebo effects are readily established without choice.
PURPOSE
We tested whether single or daily choice between two (placebo) treatments enhanced the placebo effect for sleep difficulty relative to no choice and no treatment over a 1 week period.
METHODS
One-hundred and seventeen volunteers self-identifying with sleep difficulty were recruited under the guise of a hypnotic trial and randomized to one of the four groups. Self-reported outcomes included insomnia severity, fatigue, total sleep time (TST), sleep onset latency (SOL), perceived sleep quality (PSQ), and treatment satisfaction. Objective TST and SOL were assessed in a subsample via actigraphy.
RESULTS
Overall, placebo treatment significantly improved insomnia severity, fatigue, and PSQ, confirming a placebo effect on these outcomes. However, both traditional and Bayesian analysis indicated no benefit of choice on the placebo effect on any sleep outcome. Mediation analysis of the overall placebo effect indicated that expectancy completely mediated the placebo effects for insomnia severity and PSQ and partially mediated the placebo effect for fatigue.
CONCLUSION
These findings suggest that choice does not enhance the placebo effect over longer treatment periods (up to 7 days) when placebo effects are readily established without choice. As such, any benefit of choice on placebo effects may be confined to quite specific circumstances.
CLINICAL TRIALS REGISTRATION
ACTRN12618001199202.
Topics: Actigraphy; Adolescent; Adult; Anticipation, Psychological; Choice Behavior; Fatigue; Female; Humans; Male; Outcome Assessment, Health Care; Placebo Effect; Placebos; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Young Adult
PubMed: 31504091
DOI: 10.1093/abm/kaz030 -
Developmental Medicine and Child... Oct 2023Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with... (Review)
Review
Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with neurodevelopmental disorders. Here, we review the placebo effect in autism spectrum disorder (ASD). Placebo responses are widely evident in ASD clinical trials and could partly operate via so-called placebo-by-proxy, whereby caregivers or clinicians indirectly shape patient outcomes. Understanding the role of placebo effects in ASD may help discern genuine treatment effects from contextual factors in clinical trials. The much less studied nocebo effect, or negative placebo, might contribute to the experience of side effects in ASD treatments but empirical data is missing. Better knowledge about placebo and nocebo mechanisms may contribute to the development of more effective research designs, such as three-armed designs that account for natural history, and improved treatments for ASD symptoms. At a clinical level, deeper knowledge about placebo and nocebo effects may optimize the delivery of care for individuals with ASD in the future. WHAT THIS PAPER ADDS: Placebo responses are evident in autism spectrum disorder (ASD) clinical trials. Placebo responses in ASD are likely dependent on a placebo-by-proxy mechanism.
Topics: Humans; Child; Placebo Effect; Autism Spectrum Disorder; Nocebo Effect
PubMed: 36917698
DOI: 10.1111/dmcn.15574 -
Journal of Oral Rehabilitation May 2022Evidence for the nocebo effect, a phenomenon characterised by suboptimal treatment efficacy, worsening of symptoms, or the occurrence of adverse events caused by an... (Review)
Review
BACKGROUND
Evidence for the nocebo effect, a phenomenon characterised by suboptimal treatment efficacy, worsening of symptoms, or the occurrence of adverse events caused by an individual's negative treatment expectations, is growing across a multitude of medical fields. However, little attention has been paid to patients' negative expectations and the nocebo effect within dentistry.
AIM
This review summarises essential evidence of the nocebo phenomenon especially in relation to pain and drug administration. Subsequently, an overview of the current evidence of the nocebo phenomenon in the dental field is presented.
METHODS
A PubMed search was performed using keywords related to "nocebo," "placebo," "expectations," and "dentistry." In addition to the articles selected from the search, placebo/nocebo researchers and dental researchers added important references from their respective fields.
RESULTS
Although research on the nocebo effect in dentistry is limited, available current evidence suggests that the factors, which is related to the nocebo effect are likely to play a role in dental practice.
CONCLUSION
Preliminary evidence from the review warrants further investigation into the nocebo effect in dentistry. Finally, based on the general knowledge of the nocebo effect, the review indicates fruitful arrays of research into the nocebo effect in dentistry.
Topics: Dentistry; Humans; Nocebo Effect; Placebo Effect; Treatment Outcome
PubMed: 35043415
DOI: 10.1111/joor.13306 -
Pain Jan 2024This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical... (Meta-Analysis)
Meta-Analysis
This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical trials (RCTs) on painful diabetic neuropathy (PDN), updating the previous literature by a decade. Four databases were searched for PDN trials published in the past 20 years, testing oral medications, adopting a parallel-group design. Magnitude of placebo or nocebo responses, Cochrane risk of bias, heterogeneity, and moderators were evaluated. Searches identified 21 studies (2425 placebo-treated patients). The overall mean pooled placebo response was -1.54 change in the pain intensity from baseline [95% confidence interval (CI): -1.52, -1.56, I 2 = 72], with a moderate effect size (Cohen d = 0.72). The pooled placebo 50% response rate was 25% [95% CI: 22, 29, I 2 = 50%]. The overall percentage of patients with adverse events (AEs) in the placebo arms was 53.3% [95% CI: 50.9, 55.7], with 5.1% [95% CI: 4.2, 6] of patients dropping out due to AEs. The year of study initiation was the only significant moderator of placebo response (regression coefficient = -0.06, [95% CI: -0.10, -0.02, P = 0.007]). More recent RCTs tended to be longer, bigger, and to include older patients (N = 21, rs = 0.455, P = 0.038, rs = 0.600, P = 0.004, rs = 0.472, P = 0.031, respectively). Our findings confirm the magnitude of placebo and nocebo responses, identify the year of study initiation as the only significant moderator of placebo response, draw attention to contextual factors such as confidence in PDN treatments, patients' previous negative experiences, intervention duration, and information provided to patients before enrollment.
Topics: Humans; Nocebo Effect; Diabetic Neuropathies; Placebo Effect; Pain Measurement; Diabetes Mellitus
PubMed: 37530658
DOI: 10.1097/j.pain.0000000000003000