Enck Paul, Klosterhalfen Sibylle
Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany.
Front Neurosci. 2019 Mar 4;13:160. doi: 10.3389/fnins.2019.00160. eCollection 2019.
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.
多年来，人们一直推测性别是安慰剂和反安慰剂效应的一个预测因素，但这一推测是否成立却鲜有研究。我们利用了一个关于真实安慰剂/反安慰剂反应各方面的安慰剂文献数据库。2015年，我们提取了在主要医学领域（神经学、精神病学、内科）进行的75项系统评价、荟萃分析和荟萃回归。对这些荟萃分析进行筛选，看是否注意到性别差异对安慰剂/反安慰剂效应有影响：在这些分析中，只有3项显示女性性别与较高的安慰剂效应相关，这表明在随机对照试验中，性别对安慰剂效应有影响的证据不足。本次综述用另一组荟萃分析对此进行了更新，但总体结论并未改变。对于在试验安慰剂组中调查随机对照试验中不良事件（反安慰剂）报告的18项荟萃分析，情况也是如此。我们还在数据库中筛选了在实验研究中提及性别与安慰剂效应的论文，共识别出28篇报告了29项实验的论文。其结果可总结如下：（a）尽管女性对疼痛更敏感，但男性更容易产生安慰剂镇痛作用；（b）似乎条件作用能有效地引发反安慰剂效应；（c）条件作用在女性中以及对恶心特别能有效地引发安慰剂和反安慰剂效应；（d）言语暗示不足以在女性中诱导镇痛，但对男性有效。将就为什么恶心和疼痛可能更容易受到性别差异的影响，而其他症状则不然这一问题对这些结果进行讨论。最后，我们将讨论在随机对照试验中性别相关性较低与在特定实验环境中性别相关性较高之间明显的差异。我们认为，安慰剂反应在女性中主要是条件作用（学习）反应的结果，而在男性中主要可能是通过（言语）操纵预期产生的。因此，在随机对照试验中，尽管两性产生安慰剂效应的机制不同，但干预的净结果可能相同，而在实验工作中，当两条途径分开并明确探索时，这种差异可能会显现出来。
