Mechanisms of pain and placebo analgesia

研究人员将安慰剂诱导的疼痛调节描述为有意识的期望和独立作用的学习机制的结果。我们已经能够证明，期望是一个动态的实体，由我们不断的经历所塑造。学习机制是引发安慰剂镇痛效果的关键，同时也是对益处的期望和预期。我们的研究表明，当参与者之前有积极的经历（例如，服药后疼痛减轻）时，安慰剂镇痛的强度要高于消极的经历（例如，服药后疼痛增加）。这意味着，之前的经验，无论是积极的还是消极的，都会对随后的治疗结果产生持久的影响，强调疼痛经验是通过学习来调节的。神经生理学的研究结果也证实了先前经验在安慰剂反应中的重要性，说明了条件反射在早期大脑伤害性加工水平上的影响。我们已经证明，药理学条件反射增强了安慰剂镇痛，并且条件反射的效果持续数天。在后续研究中，我们也证明了条件反射试验次数越多，安慰剂镇痛持续时间越长。这些行为发现被功能性磁共振成像方法证实，表明大脑背外侧前额叶皮层区域是安慰剂镇痛作用的发起者。

Researchers have described placebo-induced modulation of pain as the result of conscious expectations and learning mechanisms acting independently. We have been able to demonstrate that expectations are a dynamic entity shaped by our ongoing experiences. Learning mechanisms are pivotal in eliciting a placebo analgesic effect along with expectations and anticipations of benefit. Our studies have shown that the magnitude of placebo analgesia is higher when the participant had a positive prior experience (e.g., reduction of pain after taking a pill) as compared to a negative experience (e.g., increase of pain after taking a pill). The implication is that prior experiences, both positive and negative, have long-lasting effects on the outcome of a subsequent treatment, underscoring that pain experience is modulated by learning. The importance of prior experience in placebo response is also confirmed by neurophysiological findings illustrating the effects of conditioning at the level of early brain nociceptive processing. We have demonstrated that pharmacological conditioning boosts placebo analgesia and that the effects of conditioning last several days. In a follow-up study, we also demonstrated that the greater the number of conditioning trials, the longer the placebo analgesia lasts. These behavioral findings are corroborated by functional magnetic resonance imaging approach indicating that the dorsolateral prefrontal cortex area of the brain acts as initiator of placebo analgesic effects. Numerous studies have indicated that placebo analgesia can be established via conditioning procedures. However, these studies have exclusively involved conditioning under continuous reinforcement. We first established that placebo analgesia can be induced by partial reinforcement. Four novel and important findings emerged. The first is that placebo analgesia can be also established under partial reinforcement. The second is that the placebo analgesia established under partial reinforcement was weaker than that established under continuous reinforcement. The third is that the placebo analgesia established under continuous reinforcement extinguished rapidly. The fourth, and perhaps most interesting, is that the placebo analgesia established under partial reinforcement appeared resistant to extinction. These findings have a number of important practical and theoretical implications. Namely, a partial reinforcement approach could be a potential method of reducing total drug dosages whilst maintaining therapeutic benefit. We have also studied the role of social learning which refers to learning by observing others, on placebo analgesia. We found that observationally-induced analgesia was similar in magnitude to that induced by directly experiencing effectiveness via conditioning and that the higher the empathy in a person, the larger the placebo analgesic effect. Importantly, empathy correlates with placebo analgesic responses only during live interpersonal interactions. The magnitude of placebo analgesia was similar after observing a video or a person suggesting that observation induces placebo analgesia and that empathy may facilitate these effects during live interactions but is not a driving force. These results challenged previous theories involving expectation and conditioning as psychological mechanisms underlying placebo mechanisms and introduced the concept and evidence that different forms of learning underlie the formation of placebo analgesia. From a psychoneurobiological viewpoint, we know that positive appraisal and expectations trigger the release of endogenous neuropeptides such as opioids, cannabinoids and oxytocin resulting in the modulation of placebo analgesia. We investigated the modulatory role of arginine vasopressin, a neuropeptide known for controlling water in the body with Avp1a and Avp1b vasopressin receptors largely expressed within the central nervous system to regulate social and stress behaviors in a sex-specific manner. Recent studies in humans have suggested that vasopressin has a sex-specific effect on conciliatory behaviors and social communication promoting different coping strategies in men and women during social interactions and stressful contexts. Given the known sexual dimorphism of this neuropeptide, we explored the role of vasopressin in modulating expectancy-induced analgesia against no treatment, oxytocin, and placebo in men and women in a randomized, double-blind, placebo controlled, parallel design trial in 108 healthy participants. We found that vasopressin significantly enhances expectancy-induced analgesia, relative to the no treatment, oxytocin and saline groups. Moreover, the vasopressin agonists potentiate expectancy-induced analgesia in a sex-specific manner. These results were independent of any intrinsic analgesic effect of vasopressin on pain tolerance. Women with lower anxiety trait scores when received vasopressin, showed sustained cortisol levels that were associated with larger analgesia indicating that stress and coping mechanisms may contribute to enhancement of expectancy-induced analgesia. We interpreted these results as the demonstration that vasopressin may trigger endogenous antinociceptive mechanisms analogous to stress-induced analgesic systems, which are evolutionarily developed for protective responses to pain. By activating the hypothalamic-pituitary-adrenal axis, vasopressin may have prompted women with low anxiety traits to engage in better stress-coping strategies that in turn lead to higher expectancy-induced analgesia. In line with studies supporting a sex-related effect of vasopressin on conciliatory behaviors and social interactions, vasopressin may have influenced the processing of verbal and nonverbal communication in women differently than men. These findings indicate a complex sex specific role of vasopressin in placebo analgesia with potentially important implications for future translational research strategies. The mechanisms by which vasopressin enhances expectancy-induced analgesia deserve further investigation. Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. We performed a comprehensive review of the literature on pain modulation in pediatrics. After highlighting crucial aspects that need to be considered in studying pain modulation in infants and children, we reviewed studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. Psychological mechanisms underlying placebo effects in children including: 1) verbally-induced expectations; 2) conditioning and learning mechanisms; 3) child-parent-physician interactions. We suggest that placebo mechanisms strongly impact therapeutic pain outcomes and can potentially be exploited clinically to improve clinical outcomes in pediatric populations. We provide recommendations for further investigating the mechanistic underpinnings of the placebo effect and exploiting its benefits for supportive therapeutic strategies. The counterpart of placebo analgesia is the nocebo phenomenon in which, negative expectations produce negative outcomes, influencing the effects of drugs and pain experience. Based on laboratory and critical reviews of the literature, we performed recently a meta-analysis of nocebo studies based on the administration of an inert treatment along with verbal suggestions of symptom worsening. We found that nocebo effects induced by verbal suggestions and conditioning were larger than in studies where nocebo effects were induced by verbal suggestions alone. These findings are similar to those reported for placebo effect, demonstrating the need for minimizing nocebo effects in medicine.