The impact of patients' pre-treatment expectations on immunosuppressive treatment outcomes in myasthenia gravis: A pilot correlational study.

INTRODUCTION/AIMS: The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia gravis (MG) the contribution of patients' pre-treatment expectations combined with an immunosuppressant drug on treatment outcomes. METHODS: This pilot correlational study involved 17 patients with generalized MG, scheduled to start immunosuppressant azathioprine. At baseline, a healthcare professional administered: (i) the Stanford Expectations of Treatment Scale; (ii) a structured checklist paper form asking patients which side-effects they expected to develop after starting azathioprine, coupled with a standardized framing of statements. Quantitative Myasthenia Gravis (QMG) score and daily dose of concomitant drugs were assessed by neurologists as clinical outcomes. Clinical outcomes and side-effects were re-assessed at 3 and 6 months, and clinical outcomes were monitored at 18 months. RESULTS: Clinically significant improvement in the QMG scores was achieved at 3 or 6 months. The level of state anxiety appeared to act as moderator of pre-treatment negative expectations (strong, positive, indicative correlation, rs = .733, p = .001). The latter were, in turn, associated with the fulfillment of side-effects that patients expected to develop with the new treatment (moderate, positive, indicative correlation, rs = .699, p = .002). No significant correlation emerged between positive and negative expectations. DISCUSSION: Our findings show a very quick clinical response and also suggest that patients' expectations and anxiety contributed to treatment outcomes, highlighting the importance of promoting safety messages and education strategies around newly introduced treatments. Future goals include evaluating a larger cohort that includes a matched control group.

Placebo and nocebo responses in painful diabetic neuropathy: systematic review and meta-analysis.

ABSTRACT: 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.

Placebo and nocebo effects and mechanisms associated with pharmacological interventions: an umbrella review.

OBJECTIVES: This review aimed to summarise the existing knowledge about placebo and nocebo effects associated with pharmacological interventions and their mechanisms. DESIGN: Umbrella review, adopting the Assessment of Multiple Systematic Reviews 2 tool for critical appraisal. DATA SOURCES: MEDLINE/PubMed, Scopus, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trial were searched in September 2022, without any time restriction, for systematic reviews, narrative reviews, original articles. Results were summarised through narrative synthesis, tables, 95% CI. OUTCOME MEASURES: Mechanisms underlying placebo/nocebo effects and/or their effect sizes. RESULTS: The databases search identified 372 studies, for a total of 158 312 participants, comprising 41 systematic reviews, 312 narrative reviews and 19 original articles. Seventy-three per cent of the examined systematic reviews were of high quality.Our findings revealed that mechanisms underlying placebo and/or nocebo effects have been characterised, at least in part, for: pain, non-noxious somatic sensation, Parkinson's disease, migraine, sleep disorders, intellectual disability, depression, anxiety, dementia, addiction, gynaecological disorders, attention-deficit hyperactivity disorder, immune and endocrine systems, cardiovascular and respiratory systems, gastrointestinal disorders, skin diseases, influenza and related vaccines, oncology, obesity, physical and cognitive performance. Their magnitude ranged from 0.08 to 2.01 (95% CI 0.37 to 0.89) for placebo effects and from 0.32 to 0.90 (95% CI 0.24 to 1.00) for nocebo effects. CONCLUSIONS: This study provides a valuable tool for clinicians and researchers, identifying both results ready for clinical practice and gaps to address in the near future. FUNDING: Università Cattolica del Sacro Cuore, Milan, Italy with the 'Finanziamento Ponte 2022' grant. PROSPERO REGISTRATION NUMBER: CRD42023392281.

What is the role of placebo in neurotherapeutics?

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.

Thirty Years of Neuroscientific Investigation of Placebo and Nocebo: The Interesting, the Good, and the Bad.

Over the past 30 years there has been a surge of research on the placebo effect using a neuroscientific approach. The interesting aspects of this effort are related to the identification of several biological mechanisms of both the placebo and nocebo effects, the latter of which is defined as a negative placebo effect. Some important translational implications have emerged both in the setting of clinical trials and in routine medical practice. One of the principal contributions of neuroscience has been to draw the attention of the scientific and medical communities to the important role of psychobiological factors in therapeutic outcomes, be they drug related or not. Indeed, many biological mechanisms triggered by placebos and nocebos resemble those modulated by drugs, suggesting a possible interaction between psychological factors and drug action. Unfortunately, this new knowledge regarding placebos has the potential of being dangerously exploited by pseudoscience.

The subthalamic nucleus and the placebo effect in Parkinson's disease.

The study of the placebo effect, or response, is related to the investigation of the psychologic component of different therapeutic rituals. The high rate of placebo responses in Parkinson's disease clinical trials provided the impetus for investigating the underlying mechanisms. Ruling out spontaneous remission and regression to the mean through the appropriate experimental designs, genuine psychologic placebo effects have been identified, in which both patients' expectations of therapeutic benefit and learning processes are involved. Specifically, placebo effects are associated with dopamine release in the striatum and changes in neuronal activity in the subthalamic nucleus, substantia nigra pars reticulata, and motor thalamus in Parkinson's disease, as assessed through positron emission tomography and single-neuron recording during deep brain stimulation, respectively. Conversely, verbal suggestions of clinical worsening or drug dose reduction induce nocebo responses in Parkinson's disease, which have been detected at both behavioral and electrophysiologic level. Important implications and applications emerge from this new knowledge. These include better clinical trial designs, whereby patients' expectations should always be assessed, as well as better drug dosage in order to reduce drug intake.

Effectiveness of a dance-physiotherapy combined intervention in Parkinson's disease: a randomized controlled pilot trial.

BACKGROUND: Physical therapies have been recommended as crucial components in Parkinson's disease (PD) rehabilitation. OBJECTIVE: The study aims to examine the effectiveness of a new dance-physiotherapy combined intervention, called DArT method, in mild PD patients. METHODS: A prospective, randomized, single-blind, controlled pilot trial was conducted on 38 mild PD patients under dopaminergic therapy. The intervention consisted in an add-on protocol: the control group received 1 h of conventional physiotherapy followed by 1 h of conventional physiotherapy each day, 3 times a week, for 5 weeks. The experimental group received 1 h of conventional physiotherapy followed by 1 h of dance class each day, 3 times a week, for 5 weeks. The week before and after the training period, patients were assessed for motor, cognitive, emotional, and sensory components of PD, with MDS-UPDRS-III as primary outcome measure. RESULTS: DArT method was associated with a 2.72-point reduction in the post-treatment MDS-UPDRS-III total score compared to control group (95% CI - 5.28, - 0.16, p = 0.038, d = 0.71), and with a 2.16-point reduction in the post-treatment MDS-UPDRS-III upper body subscore (95% CI - 3.56, - 0.76, p = 0.003, d = 1.02). Conversely, conventional physiotherapy program was associated with a 2.95-point reduction in the post-treatment trait anxiety compared to the experimental group (95% CI 0.19, 5.71, p = 0.037, d = 0.70). Withdrawal and fall rates were equal to 0% in both groups. CONCLUSION: DArT method showed to be safe, well accepted, and more effective than an intensive program of conventional physiotherapy in improving motor impairment in mild PD.

A new visual feedback-based system for the assessment of pinch force, endurance, accuracy and precision. A test-retest reliability study.

Introduction: Given that pinch is a precision grip involved in sustained submaximal activities, a Sustained Contraction (SC) task could be associated to Maximal Voluntary Contraction (MVC). To better evaluate the thumb-index system, the test-retest reliability of pinch MVC and SC, measured by a visual feedback-based pinch gauge was assessed. Methods: 26 healthy participants performed MVC and SC in two separate sessions. SC required to maintain 40%MVC as long as possible and it was evaluated in terms of time, accuracy (Mean Distance between force trace and target force, MD), precision (Coefficient of Variability of force trace, CV). MD and CV analyses were conducted dividing the SC task into three equivalent time stages (beginning, middle, exhaustion). Relative Reliability (RR) was measured by Intraclass Correlation Coefficient, and Absolute Reliability (AR) was measured by Standard Error of Measurement and by Bland-Altman plot. Results: MVC and Time showed high RR and AR in both hands. RR of MD and CV in right hand was excellent in the beginning and middle stages, and fair in the exhaustion one, showing decreasing reliability as fatigue increases. In the left hand RR of MD and CV was generally lower. MD showed excellent reliability in the beginning stage and good reliability in the other stages. CV showed fair relative reliability at both beginning and middle stages, excellent in the last one. Conversely, it was observed high AR of MD and CV in all stages in both hands. Conclusions: All indices are reliable to assess motor control of thumb-index pinch in both hands.

Understanding the mechanisms of placebo and nocebo effects.

Although placebos have long been considered a nuisance in clinical research, over recent years they have become an active and productive field of research. Indeed, the placebo effect represents an elegant model to understand how the brain works. It is worth knowing that there is not a single but many placebo effects, with different mechanisms across different systems, medical conditions and therapeutic interventions. For example, brain mechanisms of expectation, anxiety and reward are all involved, as well as a variety of learning phenomena. There is also some experimental evidence of different genetic variants in placebo responsiveness. Pain and Parkinson’s disease represent the most productive models to better understand the neurobiology of the placebo effect. In these medical conditions the neural networks involved have indeed been identified: that is, opioid, cannabinoid, cholecystokinin, cyclooxygenase, and dopamine modulatory networks in pain; and part of the basal ganglia circuitry in Parkinson’s disease. Overall, there is today compelling evidence that placebos and drugs share common biochemical pathways and activate the same receptor pathways, which suggests possible interference between social stimuli and therapeutic rituals on one hand and pharmacological agents on the other. The same holds true for the nocebo effect, the opposite phenomenon of placebo. The assessment of patients’ expectations should become the rule in clinical trials in order to allow us a better interpretation of therapeutic outcomes when comparing placebo and active treatment groups. Administering drugs covertly is another way to identify the placebo psychobiological component without the administration of any placebo, and this provides important information on the role of patient’s expectations in the therapeutic outcome. A further in-depth analysis of placebo and nocebo phenomena will certainly provide important information in the near future for a better understanding of human biology, medicine and society.

Nocebo and the contribution of psychosocial factors to the generation of pain.

The biopsychosocial model claims that illness is generated by biological, psychological, and social factors. The nocebo response, particularly nocebo hyperalgesia, is an excellent model and approach to understand these effects and their psychophysiological underpinnings, as nocebos are made of negative psychological and social factors, such as negative expectations and social interactions. There is today experimental evidence that nocebos can create symptoms and illness from nothing, in particular pain, whereby a combination of biological, psychological and social factors interact with each other in the generation of the global painful experience. Several biochemical pathways have been identified, e.g. cholecystokinin and cyclooxygenase, and the activation of these mechanisms has been specifically investigated in the field of pain, analgesia and hyperalgesia. The study of placebo and nocebo oxygen at high-altitude has been crucial to unravel these mechanisms, as reduction of oxygen pressure (hypoxia) leads to headache pain. Indeed, the investigation of oxygen-related conditions, such as hypoxia, represents today an excellent approach to understand how nocebos can contribute to generate illness and pain. In this review we discuss old and new findings that help us better understand the interplay between biology and psychology.

Verbal communication about drug dosage balances drug reduction in Parkinson's disease: Behavioral and electrophysiological evidences.

INTRODUCTION: Changing drug dosage is common in clinical practice. Recent evidence showed that psychological factors may affect the therapeutic outcome. The aim of this study is to test whether verbal communication about drug dosage changes motor performance and fatigue in Parkinson's Disease (PD) patients. METHODS: We performed clinical (Unified PD Rating Scale), motor (number of finger flexions and perceived fatigue), and electrophysiological measurements (readiness potential, RP) in PD patients during medication-off and medication-on conditions in three groups. The first group got a full dose of l-dopa and was told it was a full dose. The second group got half dose and was told it was half dose. The third group got half dose, but it was told it was a full standard dose. RESULTS: We found that overt half dose was less effective than the full dose for clinical improvement, motor performance, and readiness potential. However, if half dose was given along with verbal instructions that it was a full dose, clinical improvement, motor performance and readiness potential were not significantly different from the full dose. CONCLUSIONS: Our findings indicate that verbal communication about dose reduction is as effective as the 50% dose reduction itself, demonstrating that deceptive information about the dose may have an important impact on the therapeutic outcome. Moreover, the supplementary motor area, source of the RP, seems to be involved in this psychological effect.

The placebo response in myasthenia gravis assessed by quantitative myasthenia gravis score: A meta-analysis.

INTRODUCTION: This meta-analysis investigates the placebo response in generalized myasthenia gravis (MG) trials by means of Quantitative Myasthenia Gravis (QMG) scores. METHODS: PubMed, Scopus, Web of Science, Cochrane Controlled Trial Register, and EMBASE were searched. QMG score, dropouts rate, adverse events (AEs), and AEs responsible for dropouts were examined, together with treatment moderators. RESULTS: The magnitude of placebo response showed an effect size of 0.24, which was significantly lower than 0.67 of the drug response (P = 0.019). Furthermore, the forest plot revealed that, overall, active treatments showed a significantly higher impact on QMG scores than placebos. CONCLUSIONS: Placebo and drug responses in MG trials are small and moderate, respectively. The lack of MG trials with a pure placebo arm or a no-treatment control arm made it impossible to disentangle improvements due to the placebo psychological effect from other effects such as natural history and/or regression to the mean. Muscle Nerve 59:671-678, 2019.

The placebo effect on bradykinesia in Parkinson's disease with and without prior drug conditioning.

BACKGROUND: Placebo effects represent a major drawback in clinical trials, and their magnitude hampers the development of new treatments. Previous research showed that prior exposure to active treatments increases the placebo response for muscle rigidity in Parkinson's disease. METHODS: We investigated the effects of prior exposure to apomorphine on the placebo response of another cardinal symptom of Parkinson's disease, bradykinesia, by a movement time analyzer. RESULTS: We found no placebo response if the placebo was given for the first time, whereas the placebo response was substantial after prior pharmacological conditioning with apomorphine. CONCLUSIONS: These findings indicate that prior exposure to drugs is a critical factor in the occurrence and magnitude of placebo effects. These learning effects should be carefully assessed in clinical trials in which patients receive the active treatment first and then are randomized. Indeed, this sequence may generate high placebo responders. © 2017 International Parkinson and Movement Disorder Society.

Why We should Assess Patients' Expectations in Clinical Trials.

Most of the analgesic clinical trials have failed to succeed over the past years because of the occurrence of large placebo responses. Patients' expectations about the therapeutic benefit represent a major determinant of the placebo response. Therefore, assessing patients' expectations should become the rule in any clinical trial. This would allow us to better interpret therapeutic outcomes when comparing placebo and verum groups.

Placebo response in pain, fatigue, and performance: Possible implications for neuromuscular disorders.

The placebo response in neuromuscular disorders is not well understood. The only available data regarding its underlying mechanisms are related to neuropathic pain. In this review, we describe the factors that contribute to improved outcomes in the placebo arm, with specific attention to pain and fatigue, as well as some of the most important psychobiological mechanisms that may explain such a response. This approach may also improve our insight into the symptomatology and therapeutic responses of other neuromuscular disorders. The fact that >90% of tested analgesics for neuropathic pain have failed in advanced phases of clinical trials should prompt a greater investment of effort and resources into understanding the mechanisms and impact of placebos in clinical research. Such an endeavor will help improve the design of clinical trials and will provide information that informs clinical neuromuscular practice. Muscle Nerve 56: 358-367, 2017.

Teaching neurons to respond to placebos.

KEY POINTS: We analysed the placebo response at the single-neuron level in the thalamus of Parkinson patients to see the differences between first-time administration of placebo and administration after pharmacological pre-conditioning. When the placebo was given for the first time, it induced neither clinical improvement, as assessed through muscle rigidity reduction at the wrist, nor neuronal changes in thalamic neurons. However, if placebo was given after two, three or four prior administrations of an anti-Parkinson drug, apomorphine, it produced both clinical and neuronal responses. Both the magnitude and the duration of these placebo responses depended on the number of prior exposures to apomorphine, according to the rule: the greater the number of previous apomorphine administrations, the larger the magnitude and the longer the duration of the clinical and neuronal placebo responses. These findings show that learning plays a crucial role in the placebo response and suggest that placebo non-responders can be turned into placebo responders, with important clinical implications. ABSTRACT: Placebos have been found to affect the patient's brain in several conditions, such as pain and motor disorders. For example, in Parkinson's disease, a placebo treatment induces a release of dopamine in the striatum and changes the activity of neurons in both thalamic and subthalamic nuclei. The present study shows that placebo administration for the first time induces neither clinical nor neuronal improvement in Parkinson patients who undergo implantation of electrodes for deep brain stimulation. However, this lack of placebo responsiveness can be turned into substantial placebo responses following previous exposure to repeated administrations of the anti-Parkinson agent apomorphine. As the number of apomorphine administrations increased from one to four, both the clinical response and the neuronal activity in the ventral anterior and anterior ventrolateral thalamus increased. In fact, after four apomorphine exposures, placebo administration induced clinical responses that were as large as those to apomorphine, along with long-lasting neuronal changes. These clinical placebo responses following four apomorphine administrations were again elicited after a re-exposure to a placebo 24 h after surgery, but not after 48 h. These data indicate that learning plays a crucial role in placebo responsiveness and suggest that placebo non-responders can be turned into responders, with important implications in the clinical setting.