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The Clinical Implications of Nocebo Effects for Biosimilar Therapy.

Nocebo effects encompass negative responses to inert interventions in the research setting and negative outcomes with active treatments in the clinical research or practice settings, including new or worsening symptoms and adverse events, stemming from patients' negative expectations and not the pharmacologic action of the treatment itself. Numerous personality, psychosocial, neurobiological, and contextual/environmental factors contribute to the development of nocebo effects, which can impair quality of life and reduce adherence to treatment. Biologics are effective agents widely used in autoimmune disease, but their high cost may limit access for patients. Biosimilar products have gained regulatory approval based on quality, safety, and efficacy comparable to that of originator biologics in rigorous study programs. In this review, we identified gaps in patients' and healthcare professionals' awareness, understanding, and perceptions of biosimilars that may result in negative expectations and nocebo effects, and may diminish their acceptance and clinical benefits. We also examined features of nocebo effects with biosimilar treatment that inform research and clinical practices. Namely, when biosimilars are introduced to patients as possible treatment options, we recommend adoption of nocebo-reducing strategies to avoid negative expectations, including delivery of balanced information on risk-benefit profiles, framing information to focus on positive attributes, and promoting shared decision-making processes along with patient empowerment. Healthcare professionals confident in their knowledge of biosimilars and aware of bias-inducing factors may help reduce the risk of nocebo effects and improve patients' adherence in proposing biosimilars as treatment for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

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Physical functioning and mindfulness skills training in chronic pain: a systematic review.

The importance of improved physical function as a primary outcome in the treatment of chronic pain is widely accepted. There have been limited attempts to assess the effects mindfulness skills training (MST) has on objective outcomes in chronic pain care.

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Placebo analgesia induced by verbal suggestion in the context of experimentally induced fear and anxiety.

The role of state anxiety and state fear in placebo effects is still to be determined. We aimed to investigate the effect of fear of movement-related pain (FMRP) and contextual pain related anxiety (CPRA) on the magnitude of placebo analgesia induced by verbal suggestion. Fifty-six female participants completed a modified voluntary joystick movement paradigm (VJMP) where half participated in a predictable pain condition (PC), in which one of the joystick movements is always followed by pain and the other movement is never followed by pain, and half in an unpredictable pain condition (UC), in which pain was delivered unpredictably. By varying the level of pain predictability, FMRP and CPRA were induced in PC and UC respectively. Colour stimuli were presented at the beginning of each trail. Half of the participants were verbally informed that the green or red colour indicated less painful stimuli (experimental groups), the other half did not receive any suggestion (control groups). We measured self-reported pain intensity, expectancy of pain intensity (PC only), pain related fear and anxiety (eyeblink startle response and self-ratings) and avoidance behaviour (movement-onset latency and duration). The results indicate that the placebo effect was successfully induced in both experimental conditions. In the PC, the placebo effect was predicted by expectancy. Despite the fact that FMRP and CPRA were successfully induced, no difference was found in the magnitude of the placebo effect between PC and UC. Concluding, we did not find a divergent effect of fear and anxiety on placebo analgesia.

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Evaluating Cortical Alterations in Patients With Chronic Back Pain Using Neuroimaging Techniques: Recent Advances and Perspectives.

Chronic back pain (CBP) is a leading cause of disability and results in considerable socio-economic burdens worldwide. Although CBP patients are commonly diagnosed and treated with a focus on the "end organ dysfunction" (i.e., peripheral nerve injuries or diseases), the evaluation of CBP remains flawed and problematic with great challenges. Given that the peripheral nerve injuries or diseases are insufficient to define the etiology of CBP in some cases, the evaluation of alterations in the central nervous system becomes particularly necessary and important. With the development of advanced neuroimaging techniques, extensive studies have been carried out to identify the cortical abnormalities in CBP patients. Here, we provide a comprehensive overview on a series of novel findings from these neuroimaging studies to improve our understanding of the cortical abnormalities originated in the disease. First, CBP patients normally exhibit central sensitization to external painful stimuli, which is indexed by increased pain sensitivity and brain activations in pain-related brain regions. Second, long-term suffering from chronic pain leads to emotional disorders, cognitive impairments, and the abnormalities of the relevant brain networks among CBP patients. Third, CBP is associated with massive cortical reorganization, including structural, functional, and metabolic brain changes. Overall, a deep insight into the neural mechanisms underlying the development and outcome of CBP through more sophisticated neuroimaging investigations could not only improve our current understanding of the etiology of CBP but also facilitate the diagnosis and treatment of CBP based on precision medicine.

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Hypnosis for cingulate-mediated analgesia and disease treatment.

Hypnosis is a technique that induces changes in perceptual experience through response to specific suggestions. By means of functional neuroimaging, a large body of clinical and experimental studies has shown that hypnotic processes modify internal (self-awareness) as well as external (environmental awareness) brain networks. Objective quantifications of this kind permit the characterization of cerebral changes after hypnotic induction and its uses in the clinical setting. Hypnosedation is one such application, as it combines hypnosis with local anesthesia in patients undergoing surgery. The power of this technique lies in the avoidance of general anesthesia and its potential complications that emerge during and after surgery. Hypnosedation is associated with improved intraoperative comfort and reduced perioperative anxiety and pain. It ensures a faster recovery of the patient and diminishes the intraoperative requirements for sedative or analgesic drugs. Mechanisms underlying the modulation of pain perception under hypnotic conditions involve cortical and subcortical areas, mainly the anterior cingulate and prefrontal cortices as well as the basal ganglia and thalami. In that respect, hypnosis-induced analgesia is an effective and highly cost-effective alternative to sedation during surgery and symptom management.

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Acupuncture for the Treatment of Pain – A Mega-Placebo?

Several control conditions, such as penetrating sham acupuncture and non-penetrating placebo needles, have been used in clinical trials on acupuncture effects in chronic pain syndromes. All these control conditions are surprisingly effective with regard to their analgesic properties. These findings have fostered a discussion as to whether acupuncture is merely a placebo. Meta-analyses on the clinical effectiveness of placebo revealed that placebo interventions in general have minor, clinically important effects. Only in trials on pain and nausea, including acupuncture studies, did placebo effects vary from negligible to clinically important. At the same time, individual patient meta-analyses confirm that acupuncture is effective for the treatment of chronic pain, including small but statistically significant differences between acupuncture and sham acupuncture. All acupuncture control conditions induce , a distinct stimulation associated with pain and needling which has been shown to be a nociceptive/pain stimulus. Acupuncture therefore probably activates the pain matrix in the brain in a bottom-up fashion via the spino-thalamic tract. Central nervous system effects of acupuncture can be modulated through expectations, which are believed to be a central component of the placebo response. However, further investigation is required to determine how strong the influence of placebo on the attenuation of activity in the pain matrix really is. A meta-analysis of individual participant functional magnetic imaging data reveals only weak effects of placebo on the activity of the pain network. The clinical acupuncture setting is comprised of a combination of a distinct neurophysiological stimulus, the needling stimulus/experience, and a complex treatment situation. A broader definition of placebo, such as that proposed by Howick (2017) acknowledges a role for expectation, treatment context, emotions, learning, and other contextual variables of a treatment situation. The inclusion of particular treatment feature as a definitional element permits a contextual definition of placebo, which in turn can be helpful in constructing future clinical trials on acupuncture.

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Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain.

Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.

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Development And Early Feasibility Testing Of A Mind-Body Physical Activity Program For Patients With Heterogeneous Chronic Pain; The GetActive Study.

Increasing physical function is a challenging, yet imperative goal of pain management programs. Physical activity can improve physical function, but uptake is low due to chronic pain misconceptions, poor pain management skills, and doing too much too soon.

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Does Sex/Gender Play a Role in Placebo and Nocebo Effects? Conflicting Evidence From Clinical Trials and Experimental Studies.

Sex has been speculated to be a predictor of the placebo and nocebo effect for many years, but whether this holds true or not has rarely been investigated. We utilized a placebo literature database on various aspects of the genuine placebo/nocebo response. In 2015, we had extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine). These meta-analyses were screened for whether sex/gender differences had been noted to contribute to the placebo/nocebo effect: in only 3 such analyses female sex was associated with a higher placebo effect, indicating poor evidence for a contribution of sex to it in RCTs. This was updated with another set of meta-analyses for the current review, but did not change the overall conclusion. The same holds true for 18 meta-analyses investigating adverse event (nocebo) reporting in RCT in the placebo arm of trials. We also screened our database for papers referring to sex/gender and the placebo effect in experimental studies, and identified 28 papers reporting 29 experiments. Their results can be summarized as follows: (a) Despite higher sensitivity of pain in females, placebo analgesia is easier to elicit in males; (b) It appears that conditioning is effective specifically eliciting nocebo effects; (c) Conditioning works specifically well to elicit placebo and nocebo effects in females and with nausea; (d) Verbal suggestions are not sufficient to induce analgesia in women, but work in men. These results will be discussed with respect to the question why nausea and pain may be prone to be responsive to sex/gender differences, while other symptoms are less. Lastly, we will discuss the apparent discrepancy between RCT with low relevance of sex, and higher relevance of sex in specific experimental settings. We argue that the placebo response is predominantly the result of a conditioning (learning) response in females, while in males it predominantly may be generated via (verbal) manipulating of expectancies. In RCT therefore, the net outcome of the intervention may be the same despite different mechanisms generating the placebo effect between the sexes, while in experimental work when both pathways are separated and explicitly explored, such differences may surface.

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Topical Review: Basic Psychological Needs in Adolescents with Chronic Pain-A Self-Determination Perspective.

This topical review outlines the resilience pathway to adaptive functioning in pediatric pain within a developmental perspective. Self-Determination Theory proposes that the satisfaction of one's basic psychological needs (for autonomy, relatedness, and competence) is crucial for understanding human flourishing and healthy development. However, the role of the basic psychological needs received little attention in a pediatric-pain population. Yet, we propose that need satisfaction may be a resilience factor and need frustration a risk factor, for living with chronic pain. In this topical review, we first discuss two major models that have been developed to understand pain-related disability: the fear-avoidance model of pain and the ecological resilience-risk model in pediatric chronic pain. Both models have been used with children and adolescents but do not include a developmental perspective. Therefore, we introduce Self-Determination Theory and highlight the potentially moderating and mediating role of the basic needs on pain-related disability in children and adolescents. Taken together, we believe that Self-Determination Theory is compatible with the fear-avoidance model of pain and the ecological resilience-risk model in pediatric chronic pain and may deepen our understanding of why some adolescents are able to live adaptively in spite of chronic pain.

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