Corrigendum: Preoperative Anxiolysis and Treatment Expectation (PATE Trial): open-label placebo treatment to reduce preoperative anxiety in female patients undergoing gynecological laparoscopic surgery – study protocol for a bicentric, prospective, randomized-controlled trial

Preoperative anxiety is a very common burden for patients before surgery, with a prevalence of up to 48% (1)(2)(3). Up to 318 million surgeries were performed worldwide in 2012, with increasing global volume (4) potentially leading to over 160 million patients being affected by anxiety in the perioperative setting. Preoperative anxiety and the associated psychological stress burden manifests in increased anesthesia requirements (5) and subsequent consequences such as haemodynamic instability, impaired postoperative cognitive and physical recovery (6), prolonged recovery time and prolonged hospital stay (7). In addition, the effects persists after surgery, leading to increased postoperative pain (8,9), which is a crucial risk factor for persistent postoperative pain (10). Moreover, higher preoperative anxiety is associated with increased opioid postoperative consumption (11) and a lower quality of life after surgery (8,9). Also, preoperative anxiety appears to be predictor of the occurrence and level of postoperative anxiety (12). Consequently, perioperative anxiety incorporates the anxiety that occurs both before and after a surgical procedure.Female gender and gynecological surgery are associated with more prevalent and severe preoperative anxiety (13), making this patient group of particular interest. Reducing preoperative anxiety can improve surgical outcomes, shorten hospital stay and reduce negative impact on quality of life, calling for interventions aimed at improving preoperative anxiety. Current treatment regimens are mostly based on pharmacological interventions with unfavorable side effects (14), resulting in a decrease in prescriptions (3,6). Therefore, anesthesiologists have a crucial responsibility in guiding patients through the process between preoperative anxiety, the anesthetic as well as surgical procedure, limited treatment options and uncertain treatment success.Placebo research already provides convincing evidence that psychological preparation for surgery has a positive effect on postoperative pain and the length of hospital stay (15). Experimental and clinical studies reveal clinically relevant treatment effects on anxiety or pain elicited by positive treatment expectations, for example by placebo pills or placebo interventions (2,(16)(17)(18)(19). Negative expectation effects modulated by anxiety, demonstrably shape treatment outcomes, including patient-reported pain and treatment outcome (20)(21)(22). In addition, abdominal surgery can cause visceral pain, deep in the abdomen, and superficial somatic pain (23), and especially visceral pain is substantially amplified by negative emotions and cognitions, such as fear (24) or stress (25).Placebo treatments without deception, known as open-label placebo ("OLP"), meaning patients know and agree that they are receiving a placebo, can also produce positive treatment effects (26)(27)(28)(29). A meta-analysis of OLPs in patients with back pain, cancerrelated fatigue, attention-deficit hyperactivity disorder, allergic rhinitis, major depression, irritable bowel syndrome, and menopausal hot flushes found an overall significant, moderatesized effect of OLPs in these eleven RCTs. Such effects also include reducing test anxiety and improving self-management skills like coping, self-efficacy, introspection, hope, and self verbalization (30). Beyond that, taking OLPs alleviated pain after their administration and reduced the need for analgesics after surgery (31,32). Positive and negative expectancy effects on treatment outcome also include placebo hypoalgesia, which refers to a reduction in perceived pain due to the psychological effects of receiving a placebo believed to be an analgesic (33), and have great potential for use in clinical settings.Several mechanisms are currently recognized as underlying expectancy effects: Verbal information or instruction provided by healthcare professionals (cognitive model), classical conditioning (associative learning) and social learning (observational learning) (16), which generate the expectation-mediated placebo effect (34). The specific mechanisms underlying the effects of OLPs are not yet fully understood (35). However, there is evidence that these mechanisms are similar to those of deceptive placebo. When OLPs are used as an adjunctive treatment, the effect may rely on placebo responses induced by classical conditioning (36). Also, the effects of OLPs are often elicited by verbal suggestion, highlighting the important role of doctor-patient interaction and cognitive processing in the efficacy of OLP. In contrast to deceptive placebos, OLP treatments do not require patients to be blinded and promote awareness of the treatment, thereby enhancing autonomy and potentially activating the body's self-regulatory mechanisms through conditioned responses (37). Furthermore, it is hypothesized that the success of OLP treatments is highly dependent on the active participation of the patient, whereby the recognition of the placebo ("the pill is without medication but not without effect") may require cognitive flexibility to effectively reconcile the paradoxical information (38). Another theoretical framework for OLPs is the "Bayesian brain" model, which suggests that OLP helps to resolve cognitive dissonance by adjusting expectations based on new evidence (39). Given the limited knowledge of the mechanisms, the patients' perspective on this novel treatment is of particular interest for the future understanding.Treatment expectations can also arise from previous treatment experiences, as well as information from the media or peers. Our research group has investigated the modulation of expectations by verbal instructions and conditioning in experimental human and patient studies (17,21,32,40,41), but mainly experimental studies on observational learning in placebo or nocebo treatment have been conducted (33). However, we have also begun to investigate observational learning in patient populations. We were able to provide evidence that clinically meaningful effects can be achieved by patients observing placebo effects in an actor patient and changing expectations in chronic pain patients (42). Therefore, the encouraging benefits of observational learning derived from preclinical research provide an incentive to further investigate the role of observational learning as an important objective of our clinical trial concept and design in this patient population.Reducing anxiety in the preoperative period is of utmost importance in order to reduce the risk of perioperative complications and ultimately postoperative pain after surgery. Treatment expectations have not yet been systematically studied, although a refined assessment of positive and negative expectations may complement other psychosocial risk factors in determining individual risk for adverse health outcomes, e.g. based on concern of adverse events or low self-efficacy expectations regarding the ability to cope with preoperative anxiety and postoperative pain. More importantly, it appears that expectations can be optimized. The aim of this project is to increase knowledge regarding how treatment expectations and related mechanisms can be specifically improved in a clinical context in order to improve treatment outcomes. Therefore, we designed a bicentric randomized-controlled clinical trial dedicated to elucidate the optimization of treatment expectations using OLPs to reduce preoperative anxiety and to improve postoperative outcomes in gynecological patients. Patients will be randomized into three groups prior to laparoscopic gynecological surgery. The design allows for testing the effects of the OLP versus standard care. In addition, we will test whether the effects of OLP can be enhanced by social observational learning, e.g. via a video presenting information about OLP from a satisfied patient. The primary outcome will be preoperative anxiety. Secondary outcomes will include postoperative visceral and somatic pain, sedation requirements and analgesic consumption. 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The impact on preoperative anxiety and postoperative visceral and somatic postoperative pain outcomes will be the administration of can to positive outcomes without side effects and treatment of preoperative anxiety is the from clinical placebo research have the potential to improve outcomes and patient in the surgical setting.