Roles in practice: 1.2: Communicator: Articles & papers

Abstract
Surgical ambition is rising, with the Royal College of Surgeons reporting an increase in the number of procedures by a million over the past decade (Royal College of Surgeons. Surgery and the NHS in Numbers. Available from https://www.rcseng.ac.uk). Underpinning, this is a rapidly growing population, especially those in the over 85 age group, coupled with rising perioperative expertise; options for surgery are now present where conditions were once managed conservatively. Matching the right patient to the right procedure has never been so pertinent (Bader, Am Soc Anesthesiol 78(6), 2014). At the heart of these increasingly complex decisions, which may prove fatal or result in serious morbidity, lies the aspiration of shared decision-making (SDM) (Glance et al., N Engl J Med 370:1379-81, 2014). Shared decision-making is a patient-centred approach taking into account the beliefs, preferences and views of the patient as an expert in what is right for them, supported by clinicians who are the experts in diagnostics and valid therapeutic options (Coulter and Collins, Making shared decision-making a reality: no decision about me, without me, 2011). It has been described as the pinnacle of patient-centred care (Barry et al., N Engl J Med 366:780-1, 2012). In this commentary, we explore further the concept of shared decision-making, supported by a recent article which highlights critical deficits in current perioperative practice (Ankuda et al., Patient Educ Couns 94(3):328-33, 2014). This article was chosen for the purposes of this commentary as it is a large study across several surgical specialties investigating preoperative shared decision-making, and to our knowledge, the only of this kind.
Keywords: Education; Improvement Science; Patient-centred care; Shared decision-making.

Abstract
The increasing age and subsequent medical complexity of patients presenting for surgery grants the opportunity to examine the processes and delivery of peri-operative care. There is a need to redesign peri-operative pathways allowing room for shared decision making and personalised, evidence-based care. In times of financial constraint, this is no easy task. However, neglecting to transform services now may lead to challenges in the sustainability of the provision of peri-operative care in the long-term. Challenges in redesigning peri-operative care pathways include identification and optimisation of those at highest peri-operative risk to inform the difficult conversations surrounding the appropriateness of surgery. The moral burden of these conversations on patient and professionals alike is increasingly recognised and managing this issue requires innovative models of collaborative, multidisciplinary and interprofessional working. To operate or not can be a challenging question to answer with a number of different perspectives to consider; not least that of the patient.

Keywords: frailty; peri-operative care; peri-operative medicine; prehabilitation; risk assessment; shared decision making.

Abstract
This review on shared decision-making comes at a time when international healthcare policy, domestic law and patient expectation demand a bringing-together of the patient's values and preferences with the physician's expertise to determine the best bespoke care package for the individual. Despite robust guidance in terms of consent, the anaesthetic community have lagged behind in terms of embracing the patient-focused rather than doctor-focused aspects of shared decision-making. For many, confusion has arisen due to a conflation of informed consent, risk assessment, decision aids and shared decision-making. Although they may well be linked, they are discrete entities. The obstacles to delivering shared decision-making are many. Lack of time is the most widely cited barrier from the perspective of physicians across specialties, with little time available to the anaesthetist at the day-of-surgery pre-operative visit. A more natural place to start the process may be the pre-operative assessment clinic, especially for the 'high-risk' patient. Yet shared decision-making is for all, even the 'low-risk' patient. Another barrier is the flow and the focus of the typical anaesthetic consultation; the truncated format presents the danger of a cursory, 'time-efficient' and mechanical process as the anaesthetist assesses risk and determines the safest anaesthetic. As patients have already decided to proceed with therapy or investigation and may be more concerned about the surgery than the anaesthesia, it is often assumed they will accept whatever anaesthetic is offered and defer to the clinician's expertise - without discussion. Furthermore, shared decision-making does not stop at time of anaesthesia for the peri-operative physician. It continues until discharge and requires the anaesthetist to engage in shared decision-making for prescribing and deprescribing peri-operative medicines.

Identify evidence and narrative-based practices that promote clinician presence, a state of awareness, focus, and attention with the intent to understand patients.

Infographics about talking to adult patients with a serious illness and at risk of deterioration.

Abstract
The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.

Abstract
Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

Skills and effort are key

Abstract
Background: The use of negative words, such as 'sting' and 'pain', can increase patient pain and anxiety. We aimed to determine how pain scores compare with comfort scores and how the technique of pain assessment affects patient perceptions and experiences after operation.

Methods: After Caesarean section, 300 women were randomized before post-anaesthesia review. Group P women were asked to rate their pain on a 0-10-point verbal numerical rating scale (VNRS), where '0' was 'no pain' and '10' was 'worst pain imaginable'. Group C women were asked to rate comfort on a 0-10-point VNRS, where '0' was 'no comfort' and '10' was 'most comfortable'. All women were asked whether the Caesarean wound was bothersome, unpleasant, associated with tissue damage, and whether additional analgesia was desired.

Results: The median (inter-quartile range) VNRS pain scores was higher than inverted comfort scores at rest, 2 (1, 4) vs 2 (0.5, 3), P=0.001, and movement, 6 (4, 7) vs 4 (3, 5), P<0.001. Group P women were more likely to be bothered by their Caesarean section, had greater VNRS 'Bother' scores, 4 (2, 6) vs 1 (0, 3), P<0.001, perceived postoperative sensations as 'unpleasant' [relative risk (RR) 3.05, 95% confidence interval (CI) 2.20, 4.23], P<0.001, and related to tissue damage rather than healing and recovery (RR 2.03, 95% CI 1.30, 3.18), P=0.001. Group P women were also more likely to request additional analgesia (RR 4.33, 95% CI 1.84, 10.22), P<0.001.

Conclusions: Asking about pain and pain scores after Caesarean section adversely affects patient reports of their postoperative experiences.

Abstract
The language structures used by antenatal educators have not been previously researched in the context of antenatal childbirth classes. Epidural analgesia for labour is a common, and a frequently asked about, component of antenatal education for parents in hospitals providing maternity care.

Aim of the study: We aimed to identify the way information is described and presented by childbirth educators to assess content and determine which language structures such as metaphor, suggestion, information and storytelling are utilized.

Design: This observational study of antenatal education was conducted at a single tertiary referral center for maternity care in Western Sydney, Australia. All three childbirth educators agreed to be video recorded whilst providing information to parents during antenatal classes. Audio data was subsequently transcribed and then analysed by two researchers, independently categorising the various language structures and types of information provided. For the purposes of the current study, data concerning a single topic was used for the analysis-'epidural analgesia for labour'.

Findings: Language structures used were highly variable between educators, as was the content and time taken for the information being provided.

Conclusion and recommendations: Our findings represent a first attempt to identify baseline information used in the clinical setting of antenatal education in order to categories communication structures used. This study has identified areas for further improvements and consistency in the way educators provide information to parents and has important implications for future midwifery practice, education and research.

Abstract
Anaesthetists have traditionally focused on technological and pharmacological advances when considering the provision of anaesthetic care. Anaesthetists are expected to be able to communicate effectively with peers, patients, their families and others in the medical community; however, few details are provided regarding how this might be achieved. Recent evidence suggests that communication practices should include a consideration of conscious and subconscious processes and responses. This model has potential relevance when learning and teaching how to communicate effectively in the stressful environment of anaesthetic clinical practice, and includes: reflective listening; observing; acceptance; utilisation; and suggestion. Understanding these processes could allow the development of a learnable framework for effective communication when the usual strategies are not working. This concept could also be used to facilitate communicating with surgeons and other colleagues, with potential benefits to patients.

Abstract
Anaesthetists are key members of teams caring for burn-injured children in almost every aspect of their management. Their role can involve initial resuscitation, intensive care, analgesia, and anaesthesia for multiple procedures both acutely and subsequently for scar management. As key members of burns management teams, effective communication with patients and their families as well as other members of the burn care team is vital. There is little guidance, however, addressing how the anaesthetist might communicate and optimise anaesthetic burns care of children pre-, intra-, and postoperatively. Advances in the understanding of the neurobiology of communication suggests that we need to consider positive (placebo) or negative (nocebo) subconscious processes. Learnable language structures GREAT (Greeting, Rapport, Expectations, Addressing concerns, Tacit agreement) and LAURS (Listening, Acceptance, Utilisation, Reframing, Suggestion) can facilitate any patient or family interaction ensuring children and their parents feel they are being heard and understood. Talking about finishing rather than starting when about to perform a potentially painful procedure can also facilitate burns care with children. Other strategies include the avoidance of nocebo communications or apologising before a painful procedure and, instead, focusing on therapeutic (placebo) alternatives. Children do not view pain in the same way as adults do, and techniques such as play therapy and hypnosis can be valuable adjuncts to traditional analgesia administration in burns care, with the added benefit of minimising side-effects. The use of regular time-outs during prolonged burns surgeries is a helpful communication strategy between the anaesthetist and other members of the burns team that can optimise patient safety. Communication is a core clinical skill in the practice of anaesthesia during paediatric burns care and is an area for future research.

Abstract
Background: Clinicians frequently warn patients of discomfort before potentially painful procedures, despite the lack of evidence that such communications are helpful. We aimed to compare two communications (one with, and the other without, a warning of a 'sting') immediately before i.v. cannulation in order to measure differences in perceived pain by patients during the procedure.

Methods: Randomly assigned patients awaiting elective surgery received a communication immediately before i.v. cannulation consisting of either 'I am going to apply the tourniquet and insert the needle in a few moments. It's a sharp scratch and it may sting a little' (Group S) or 'I am going to apply the tourniquet on the arm. As I do this many people find the arm becomes heavy, numb and tingly. This allows the drip to be placed more comfortably' (Group NS). Cannulation pain was measured by a 0-10 verbal numerical rating score (VNRS) and five-point Likert scale.

Results: Of 101 participants, 49 were allocated to Group S and 52 to Group NS. Median VNRS pain scores with inter-quartile ranges (IQR) were 1 and 2, respectively, for both groups. Median Likert scores were 3 in Group S and 2 in Group NS with an IQR of 1 for both groups (P = 0.13). Six participants vocalized pain in Group S and none in Group NS (P = 0.01). Three participants withdrew their arm spontaneously in Group S and none in Group NS (P = 0.11).

Conclusions: Warning patients of a 'sting' before i.v. cannulation may not be helpful.

Abstract
The most common cause of malpractice suits is failed communication with the patients and their families. Explore ways that better communication could lead to fewer malpractice claims and allow health care organizations to reduce litigation costs.

Abstract
Purpose: To determine what outpatients ranked highest in their anesthesia care and whether anesthesiologists could predict that ranking.

Methods: A 36 item mail-back questionnaire was administered post-operatively to 45 surgical outpatients and to 15 expert anesthesiologists. Respondents were asked to rank the three highest items from each of four lists of nine items representing pre-operative, intra-operative, pre-discharge and post-discharge outpatient anesthesia care.

Results: Complete responses were obtained from 30 outpatients and all anesthesiologists. In each phase of their care (pre-operative, intra-operative, pre-discharge and post-discharge), outpatients ranked highest those elements representing information and communication. Physical conditions of care tend to be least valued. Although anesthesiologists were able to predict what patients valued in the pre and post-discharge phases of their anesthesia care (r = 0.85 and 0.91), they undervalued the importance to patients of communication and information in pre-operative and intra-operative care (r = -0.09 and .65).

Conclusions: Our results reinforce the value that patients place in adequate communication and provision of information in all phases of outpatient anesthesia care, a value that may be underappreciated by anesthesiologists.

Abstract
Background: Clinicians traditionally warn patients of pain before peripheral i.v. cannulation (PIVC). However, using words related to pain or undesirable experiences can result in greater pain and anxiety. The use of positive words can improve pain perception and subjective patient experience. We aimed to compare the effects of three types of communication, including hypnotic communication, on pain, comfort, and anxiety in patients during PIVC.

Methods: The Effect of Language and Confusion on Pain During Peripheral Intravenous Catheterization (KTHYPE) trial is a randomised, parallel, single-blind, multicentre study of patients undergoing PIVC on the dorsal face of the hand before surgery. Patients from three hospitals were randomly allocated to one of three groups: PIVC performed with a hypnosis technique (hypnosis group), negative connotation (nocebo group), and neutral connotation (neutral group). The primary outcome measure was the occurrence of pain measured with a 0-10 numerical rating scale just after PIVC.

Results: Of the 272 subjects analysed (hypnosis, n=89; nocebo, n=92; neutral, n=91), pain after PIVC was lower in the hypnosis group (mean [standard deviation]; range) (1.5 [1.9]; 0-5) compared with the neutral (3.5 [2.3]; 0-9; P<0.0001) and nocebo groups (3.8 [2.5]; 0-10; P<0.0001). Whilst anxiety was higher and comfort lower before PIVC in the hypnosis group, anxiety decreased and comfort perception increased after PIVC when hypnosis was used.

Conclusions: This is one of the first well-designed RCTs showing a significant benefit of a hypnosis technique during a routine procedure, such as PIVC. The results could facilitate implementation of hypnosis in daily clinical care.

Clinical trial registration: NCT02662322.

Language matters as a way of respecting women’s views and ensuring that they are empowered to make decisions.

Abstract
Open ended statements such as “You may feel something now” allow for patients’ widely varying responses to stimuli and are less likely to invoke a nocebo reaction, says Baruch S Krauss

Abstract
Patients are often prepared for procedural discomforts with descriptions of pain or undesirable experiences. This practice is thought to be compassionate and helpful, but there is little data on the effect of such communicative behavior. This study assesses how such descriptions affect patients' pain and anxiety during medical procedures. The interactions of patients with their healthcare providers during interventional radiological procedures were videotaped during a previously reported 3-arm prospective randomized trial assessing the efficacy of self-hypnotic relaxation. One hundred and fifty-nine videos of the standard care and attention control arms were reviewed. All statements that described painful or undesirable experiences as warning before potentially noxious stimuli or as expression of sympathy afterwards were recorded. Patients' ratings of pain and anxiety on 0-10 numerical scales (0=No Pain, No Anxiety at All and 10=Worst Pain Possible, Terrified) after the painful event and/or sympathizing statement were the basis for this study. Warning the patient in terms of pain or undesirable experiences resulted in greater pain (P<0.05) and greater anxiety (P<0.001) than not doing so. Sympathizing with the patient in such terms after a painful event did not increase reported pain, but resulted in greater anxiety (P<0.05). Contrary to common belief, warning or sympathizing using language that refers to negative experiences may not make patients feel better. This conclusion has implications for the training in medical communication skills and suggests the need for randomized trials testing different patient-practioner interactions.

Abstract
Medical procedures and tests become a challenge when anxiety and pain make it difficult for the patient to cooperate or remain still when needed. Fortunately a short intervention with hypnoidal language at the onset of a procedure induces a positive and sustained change in the way pain and anxiety are processed. While anesthesia may appear to be a simple solution to eliminate pain, the adverse effects of pre-anesthesia anxiety on postoperative behavior and recovery are often not fully appreciated. This paper discusses options for self-hypnotic relaxation that are applicable to interactions with children. The high suggestibility of children makes it relatively easy to engage them in make-believe scenarios. Avoidance of negative suggestions is key in avoiding nocebo effects that may be difficult to overcome later. Once a child is immersed in his or her preferred scenario or hobby/activity of choice, environmental and procedural stimuli can be easily integrated in the imagery. Ego-strengthening metaphors that tie in features of strength, confidence, or resilience are particularly empowering. Even when children are fully under general anesthesia they may still have recall of what is said in the room and therefore caution in word choice should be maintained.

Abstract
Objective: To investigate the effect of therapeutic suggestions played to patients through earphones during surgery on postoperative pain and opioid use.

Design: Blinded randomised controlled study.

Setting: Five tertiary care hospitals in Germany.

Participants: 385 of 400 patients consecutively recruited from January to December 2018 who were to undergo surgery for 1-3 hours under general anaesthesia. In the per protocol analysis 191 patients were included in the intervention group and 194 patients in the control group.

Intervention: The intervention comprised an audiotape of background music and positive suggestions based on hypnotherapeutic principles, which was played repeatedly for 20 minutes followed by 10 minutes of silence to patients through earphones during general anaesthesia. Patients in the control group were assigned to a blank tape.

Main outcome measures: The main outcome was dose of opioid administered by patient controlled analgesia or nurse controlled analgesia within the first postoperative 24 hours, based on regular evaluation of pain intensity on a numerical rating scale (range 0-10, with higher scores representing more severe pain).

Results: Compared with the control group, the intervention group required a significantly (P=0.002) lower opioid dose within 24 hours after surgery, with a median of 4.0 mg (interquartile range 0-8) morphine equivalents versus 5.3 (2-12), and an effect size (Cohen's d) of 0.36 (95% confidence interval 0.16 to 0.56). The number of patients who needed opioids postoperatively was significantly (P=0.001) reduced in the intervention group: 121 of 191 (63%, 95% confidence interval 45% to 70%) patients in the intervention group versus 155 of 194 (80%, 74% to 85%) in the control group. The number needed to treat to avoid postoperative opioids was 6. Pain scores were consistently and significantly lower in the intervention group within 24 hours after surgery, with an average reduction of 25%. No adverse events were reported.

Conclusions: Therapeutic suggestions played through earphones during general anaesthesia could provide a safe, feasible, inexpensive, and non-drug technique to reduce postoperative pain and opioid use, with the potential for more general use. Based on the finding of intraoperative perception by a considerable number of patients, surgeons and anaesthetists should be careful about background noise and conversations during surgery.

Trial registration: German Clinical Trial Register DRKS00013800.

Abstract
Evidence suggests that anaesthetists' communication can affect patient experience. There is a lack of guidance for anaesthetists as to the optimal verbal communication to use during insertion of epidurals on the labour ward. We recorded the verbal communication used by 14 anaesthetists during the siting of epidural catheters in women on the labour ward; a classification of the language used was subsequently devised. We found that commands and information statements were the most common types of communication used. Individual anaesthetists differed markedly in their use of positive and negative verbal language. This classification of verbal communication that we produced may be of value in future training and research of verbal communication used by anaesthetists on the labour ward.

Abstract
Purpose: Although the importance of communication skills in anesthetic practice is increasingly recognized, formal communication skills training has hitherto dealt only with limited aspects of this professional activity. We aimed to document and analyze the informally-learned communication that takes place between anesthesia personnel and patients at induction of and emergence from general anesthesia.

Methods: We adopted an ethnographic approach based principally on observation of anesthesia personnel at work in the operating theatres with subsequent analysis of observation transcripts.

Results: We noted three main styles of communication on induction, commonly combined in a single induction. In order of frequency, these were: (1) descriptive, where the anesthesiologists explained to the patient what he/she might expect to feel; (2) functional, which seemed designed to help anesthesiologists maintain physiological stability or assess the changing depth of anesthesia and (3) evocative, which referred to images or metaphors. Although the talk we have described is nominally directed at the patient, it also signifies to other members of the anesthetic team how induction is progressing. The team may also contribute to the communication behaviour depending on the context. Communication on emergence usually focused on establishing that the patient was awake.

Conclusion: Communication at induction and emergence tends to fall into specific patterns with different emphases but similar functions. This communication work is shared across the anesthetic team. Further work could usefully explore the relationship between communication styles and team performance or indicators of patient safety or well-being.

Abstract
Background: Published work on knowledge in regional anaesthesia has focused on competence, for instance by identifying numbers of procedures required to achieve competence, or by defining criteria for successful performance of blocks. We aimed to define expertise in regional anaesthesia and examine how it is acquired.

Methods: We observed anaesthetists performing 15 regional anaesthetic blocks and analysed the resulting transcripts qualitatively and in detail.

Results: Expertise in regional anaesthesia encompasses technical fluency but also includes non-cognitive skills such as handling of the patient (communicating, anticipating and minimizing discomfort) and recognizing the limits of safe practice (particularly deciding when to stop trying to insert a block). Such elements may be underplayed by the experts who possess them. Focusing on a small number of regional anaesthetic procedures in detail (as is standard with such qualitative analytical approaches) has also allowed us to develop a model for the acquisition of expertise. In this model, trainees learn how to balance theoretical and practical knowledge by reflection on their clinical experiences, an iterative process which leads to the embedding of knowledge in the expert's personal repertoire of individual techniques.

Conclusions: Expertise in regional anaesthesia extends beyond competence at technical performance; non-cognitive elements are also vital. Further work is needed to test our learning model, and the hypothesis that learning can be enhanced by deliberate promotion of the tacit elements of 'expertise' we have described.

Abstract
Purpose: To provide a simple, practical guide to communication skills which might be useful to practising anesthesiologists.

Source: Selected citations from the literature on patient-physician communication, and the personal observations of the authors based on their reading and experiences.

Principal findings: Basic communication skills are introduced, and then their application to clinical anesthesiology described. The possible benefits resulting from the enhancement of clinical communication are outlined. Strategies for tackling four commonly-encountered situations - handling others' feelings, imparting information, explaining complex concepts simply and breaking bad news - are presented. By taking a skills-oriented approach, we hope that readers will be encouraged to view this area of their work as one that can be improved upon with continued observation and practice.

Conclusion: Communication skills can enhance medical practice and improve patient outcomes. We suggest that all anesthesiologists should give thought to their effectiveness in this area.

Abstract
The value of the practitioner's communication skills in the consultation is widely recognised. Many authors support communication skills training for general practice in such areas as public health, patient satisfaction, malpractice litigation, compliance, somatisation and clinical outcomes in chronic illness. There are many reports of the success of communication skills training worldwide for medical students, general practice trainees and experienced general practitioners.

Abstract
Objective: Despite the importance of communication skills for neurologists, specific training in this area at the residency level is often lacking. This study aimed to enhance learning of these skills and to encourage reflective practice around communication skills.

Methods: A group of 12 neurology residents participated in a series of six case-based communication skills workshops. Each workshop focused on a particular clinical scenario, including breaking bad news, discussing do-not-resuscitate orders, communicating with "difficult" patients, disclosing medical errors, obtaining informed consent for neurologic tests and procedures, and discussing life-and-death decisions with families of critically ill patients. Residents also kept reflective portfolios in which real examples of these interactions were recorded.

Results: The program was well accepted, and residents rated the workshops as effective and relevant to their practice. Analysis of residents' portfolios revealed three themes relevant to patient-physician communication: 1) communication is more successful when adequate time is allowed, 2) the ability to empathize with patients and their families is essential to successful interactions, and 3) the development of specific approaches to challenging scenarios can facilitate effective interactions. The portfolios also demonstrated that residents would engage in reflective practice.

Conclusions: Targeting of communication skills training around specific clinical scenarios using neurologic cases was well accepted and was deemed relevant to practice. The use of portfolios may promote lifelong learning in this area.

Abstract
Hippocratic Oath indicates a prevailing ethos rather than a professional approach, and it is still regarded as the cornerstone and foundation of the medical profession. Medicine in Ancient Greece was strongly influenced by the values of classical philosophy as introduced by its main representatives: Plato and Aristotle. Hippocrates himself has been recognized not only as a pioneering physician, but also as an outstanding philosopher. In his writings, he claimed that "the physician must insert wisdom in medicine" and denounced the technocratic aspect of the medical profession. The Hippocratic Oath constitutes a synopsis of the moral code of Ancient Greek medicine and contributes to the stabilization of the tri-part relationship among the physician, the patient, and the illness, as described by Hippocrates. The harmony of this interactive triangle has been deranged by several factors, such as technological evolution, public media, and cost-effective modalities with multiple consequences. In these terms, the reevaluation of the Hippocratic Oath and its time-enduring messages seems essential to reinstate the relationship between the physician and the patient under a new philosophico-medical prism.

Abstract
Nocebo refers to non-pharmacological adverse effects of an intervention. Well-intended procedural warnings frequently function as a nocebo. Both nocebo and placebo are integral to the generation of 'real' treatment effects and their associated 'real' side-effects. They are induced or exacerbated by: context; negative expectancy; and negative conditioning surrounding treatment. Since the late 1990s, the neuroscience literature has repeatedly demonstrated that the nocebo effect is mediated by discrete neurobiological mechanisms and specific physiological modulations. Although no single biological mechanism has been found to explain the nocebo effect, nocebo hyperalgesia is thought to initiate from the dorsal lateral prefrontal cortex subsequently triggering the brain's descending pain modulatory system and other pain regulation pathways. Functional magnetic resonance imaging shows that expectation of increased pain is accompanied by increased neural activity in the hippocampus and midcingulate cortex which is not observed when analgesia is expected. Functional magnetic resonance imaging studies have shown that the anterior cingulate cortex is pivotal in the perception of affective pain evoked by nocebo words. Research has also explored neurotransmitters which mediate the nocebo effect. The neuropeptide cholecystokinin appears to play a key role in the modulation of pain by nocebo. Hyperalgesia generated by nocebo also increases the activity of the hypothalamic-pituitary-adrenal axis as indicated by increases in plasma cortisol. The avoidance or mitigation of nocebo needs to be recognised as a core clinical skill in optimising anaesthesia care. Embracing the evidence around nocebo will allow for phrases such as 'bee sting' and 'sharp scratch' to be thought of as clumsy verbal relics of the past. Anaesthesia as a profession has always prided itself on practicing evidence-based medicine, yet for decades anaesthetists and other healthcare staff have communicated in ways counter to the evidence. The premise of every interaction should be 'primum non nocere' (first, do no harm). Whether the context is research or clinical anaesthesia practice, the nocebo can be ignored no longer.

Abstract
Placebo and nocebo effects are often regarded by clinicians as either a quaint reminiscence from the pre-therapeutic era, or simply as a technique for establishing the efficacy of therapeutic interventions within the locus of evidence-based practice. However, neither of these explanations sufficiently account for their complexity or their persistence and impact in clinical medicine. Placebo and nocebo effects are embedded in the very fabric of therapeutic relationships and are both a manifestation and outcome of the rituals that characterise clinical practice. They are also a stark reminder of the many personal and environmental factors, including the attitudes, beliefs and expectations of both doctor and patient, that shape the outcomes of health professional-patient interactions. We describe how recent biological and neuropsychiatric data have clarified the operation of placebo and nocebo effects in clinical practice - demonstrating the ability of the therapeutic context to modulate endogenous biological processes in a targeted manner. This, in turn, illustrates the potent philosophical and sociocultural aspects of medical praxis.

Abstract
Introduction: Nocebo effects are defined as adverse events related to negative expectations and learning processes that are involved in the modulation of the descending pain pathways. Research over the last couple of decades has illustrated that behavioral, psychoneurobiological and functional changes occur during nocebo-induced pain processing.

Objectives: We aimed to review published human and non-human research on algesia and hyperalgesia resulting from negative expectations and nocebo effects.

Methods: Herein, we searched and comprehensively reviewed scientific literature providing informative knowledge about the psychoneurobiological bases of the nocebo effect in the field of pain with an emphasis on how pain processes are shaped by both cognitive and non-cognitive factors.

Results: Negative expectations are formed through verbal suggestions of heightened pain, prior nociceptive and painful experiences and observation of pain in others. Susceptibility to the nocebo effect can be also influenced by genetic variants, conscious and nonconscious learning processes, personality traits and psychological factors. Moreover, providers' behaviors, environmental cues and the appearance of medical devices can induce negative expectations that dramatically influence pain perception and processing in a variety of pain modalities and patient populations.

Conclusion: Importantly, we concluded that nocebo studies outline how individual expectations may lead to physiological changes underpinning the central integration and processing of magnified pain signaling. Further research is needed to develop strategies that can identify nocebo-vulnerable pain patients in order to optimize the psychosocial and therapeutic context in which the clinical encounter occurs, with the ultimate purpose of improving clinical outcomes.

Abstract
Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice.

Methods: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated.

Results: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects.

Conclusions: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice

Abstract
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.

Abstract
Although there has been a lot of research looking at the placebo response, nocebo responses in the healthcare setting have been largely overlooked. This article explores the potential role of negative patient-doctor communication in facilitating nocebo responses in the medical consultation. We suggest that invalidation, that is, communicating a lack of understanding and acceptance to the patient (albeit unintentionally), is a key factor in understanding the nocebo response. This article reviews evidence from the experimental and healthcare setting, which suggests that the negative effects of invalidation may be stronger than we think.

Abstract
Medical situations are hot spots in the life of a patient with potentially long lasting effects arising from the use of either negative expressions or encouraging statements, or the lack of empathy or a positive physician-patient relationship. Health care personnel should be aware of and evaluate what patients are exposed to, hear and see. Knowing more about the effects of nocebos and negative suggestions, combined with increased attention to these matters, provides the basis for better recognition of detrimental influences in their own clinical environment and to be able to avoid, stop or neutralize them. After anamnesis patients should not be left with a focus on a negative past, but shifted to positive experiences prior to their illness, or to positive expectations in the future following surgery and rehabilitation. For example, after examining an injured leg the doctor should not turn to the computer for documentation unless he has shifted the patient's focus on the other, unimpaired leg. "Is that painful too? No? Good! Can you feel that? Yes? Perfect! Can you bend that knee, move these toes? Great! That's good." This example draws attention to the fact that negative effects (discussed in the following) substantially are dependent on the focus of the patient and thus can be affected by focus shift and distraction. Patients, their symptoms and their healing are negatively affected by the omission of placebo effects, by nocebo effects and by negative suggestions.

Abstract
Introduction: Research on learning in placebo and nocebo has relied predominantly on Pavlovian conditioning procedures. Operant learning procedures may more accurately model learning in real-life situations in which placebo and nocebo effects occur.

Objectives: To investigate the development and persistence of placebo and nocebo effects using an operant avoidance learning task.

Methods: Pain-free participants (n = 58) could learn to avoid pain by performing movements that differed in difficulty and intensity of painful stimulation. Participants performed movements in 2 contexts. In the high cost of avoidance context, pain stimulus intensity reduced with increasing movement difficulty. In the low cost of avoidance context, contingencies were reversed. Participants rated pain expectations and pain intensity. During test, movement difficulties were unchanged, but participants always received a medium-intensity pain stimulus. Placebo and nocebo effects were defined as lower/higher pain intensity ratings for trajectories that previously resulted in low/high-intensity compared with medium-intensity stimulation.

Results: As expected, participants acquired differential movement-pain expectations and differential movement choices. Testing with a medium-intensity pain stimulus quickly erased differences in movement choice across contexts, but differences in pain expectations were maintained. Pain modulation across context was in line with movement-pain expectations. However, we only observed placebo effects within the low cost of avoidance context and found no evidence of nocebo effects.

Conclusion: Operant learning can change pain expectations, pain modulation, and pain-related avoidance behavior. Persisting pain expectations suggest that acquired pain beliefs may be resistant to disconfirmation, despite self-initiated experience with novel pain-movement contingencies.

Abstract
Introduction: Nocebo-induced algesic responses occurring within clinical contexts present a challenge for health care practitioners working in the field of pain medicine.

Objectives: Following the recent research on algesic nocebo effects, the scope of this review is to develop ethically acceptable strategies to help avoid, or at least reduce, nocebo responses within clinical settings.

Methods: We reviewed relevant clinical studies that depict how patient-practitioner interactions may contribute to the reduction of nocebo responses.

Results: A strong algesic nocebo effect may adversely impact a patient's condition by causing decreases in both the efficacy and effectiveness of interventions, as well as by promoting treatment nonadherence and discontinuation. These effects may be triggered through multiple channels and can lead to significant alterations in a patient's perception of pain, consequently producing a weakening of the specific positive effects of pharmacological, psychological, or physical pain-management interventions.

Conclusion: To minimize nocebo effects in clinical settings, we identified and discussed five contextual aspects relevant to the treatment of patients with chronic pain: (1) negative patient-clinician communication and interaction during treatment; (2) emotional burden of patients during treatment with analgesic medication; (3) negative information provided via informational leaflets; (4) cued and contextual conditioning nocebo effects; and (5) patient's lack of positive information. Through an understanding of these elements, many preventive and ethically acceptable clinical actions can be taken to improve multidisciplinary pain treatment outcomes.

Abstract
The investigation of nocebo effects is evolving, and a few literature reviews have emerged, although so far without quantifying such effects. This meta-analysis investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term "nocebo." Only studies that investigated nocebo effects as the effects that followed the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen's d and Hedges' g. The overall magnitude of the nocebo effect was moderate to large (lowest g=0.62 [0.24-1.01] and highest g=1.03 [0.63-1.43]) and highly variable (range of g=-0.43 to 4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d=0.81) in mechanistic studies. In studies in which nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g=0.76 [0.39-1.14] and highest g=1.17 [0.52-1.81]) than in studies in which nocebo effects were induced by verbal suggestions alone (lowest g=0.64 [-0.25 to 1.53] and highest g=0.87 [0.40-1.34]). These findings are similar to those in the placebo literature. As the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates the importance of minimizing nocebo effects in clinical practice.

Abstract
Background: Fear of side-effects can result in non-adherence to medical interventions, such as medication and chemotherapy. Side-effect expectations have been identified as strong predictors of later perception of side-effects. However, research investigating predictors of side-effect expectations is disparate.

Objective: To identify factors associated with side-effect expectations.

Search strategy: We systematically searched Embase, Ovid MEDLINE, Global Health, PsycARTICLES, PsycINFO, Web of Science and Scopus.

Inclusion criteria: Studies were included if they investigated associations between any predictive factor and expectations of side-effects from any medical intervention.

Data extraction and synthesis: We extracted information about participant characteristics, medication, rates of side-effects expected and predictors of side-effect expectations. Data were narratively synthesized.

Main results: We identified sixty-four citations, reporting on seventy-two studies. Predictors fell into five categories: personal characteristics, clinical characteristics, psychological traits and state, presentation format of information, and information sources used. Using verbal risk descriptors (eg 'common') compared to numerical descriptors (eg percentages), having lower quality of life or well-being, and currently experiencing symptoms were associated with increased side-effect expectations.

Discussion and conclusions: Decreasing unrealistic side-effect expectations may lead to decreased experience of side-effects and increased adherence to medical interventions. Widespread communications about medical interventions should describe the incidence of side-effects numerically. Evidence suggests that clinicians should take particular care with patients with lower quality of life, who are currently experiencing symptoms and who have previously experienced symptoms from treatment. Further research should investigate different clinical populations and aim to quantify the impact of the media and social media on side-effect expectations.

Abstract
This comprehensive review summarizes and interprets the neurobiological correlates of nocebo hyperalgesia in healthy humans. Nocebo hyperalgesia refers to increased pain sensitivity resulting from negative experiences and is thought to be an important variable influencing the experience of pain in healthy and patient populations. The young nocebo field has employed various methods to unravel the complex neurobiology of this phenomenon and has yielded diverse results. To comprehend and utilize current knowledge, an up-to-date, complete review of this literature is necessary. PubMed and PsychInfo databases were searched to identify studies examining nocebo hyperalgesia while utilizing neurobiological measures. The final selection included 22 articles. Electrophysiological findings pointed toward the involvement of cognitive-affective processes, e.g., modulation of alpha and gamma oscillatory activity and P2 component. Findings were not consistent on whether anxiety-related biochemicals such as cortisol plays a role in nocebo hyperalgesia but showed an involvement of the cyclooxygenase-prostaglandin pathway, endogenous opioids, and dopamine. Structural and functional neuroimaging findings demonstrated that nocebo hyperalgesia amplified pain signals in the spinal cord and brain regions involved in sensory and cognitive-affective processing including the prefrontal cortex, insula, amygdala, and hippocampus. These findings are an important step toward identifying the neurobiological mechanisms through which nocebo effects may exacerbate pain. Results from the studies reviewed are discussed in relation to cognitive-affective and physiological processes involved in nocebo and pain. One major limitation arising from this review is the inconsistency in methods and results in the nocebo field. Yet, while current findings are diverse and lack replication, methodological differences are able to inform our understanding of the results. We provide insights into the complexities and involvement of neurobiological processes in nocebo hyperalgesia and call for more consistency and replication studies. By summarizing and interpreting the challenging and complex neurobiological nocebo studies this review contributes, not only to our understanding of the mechanisms through which nocebo effects exacerbate pain, but also to our understanding of current shortcomings in this field of neurobiological research.

Abstract
Nocebo hyperalgesia refers to increases in perceived pain that putatively result from negative expectations regarding a nocebo stimulus (eg, an inert treatment, compared with no treatment). The precise cognitive-emotional factors contributing to the origins of nocebo effects are poorly understood. We aimed to test the effects of experimentally induced pain-related fear on the acquisition and extinction of nocebo hyperalgesia in healthy participants (N = 72). Acquisition and extinction of nocebo hyperalgesia were compared between a group receiving standard nocebo conditioning (Control group) and 2 groups receiving distinct fear inductions: high intensity of pain stimulations (High-pain group) or a threat manipulation (High-threat group). During nocebo acquisition, the Control and High-threat groups were administered thermal pain stimulations of moderate intensity paired with sham electrical stimulation (nocebo trials), whereas high pain intensity was administered to the High-pain group. During extinction, equivalent pain intensities were administered across all trials. Pain-related fear was measured by eyeblink startle electromyography and self-report. Nocebo hyperalgesia occurred in all groups. Nocebo effects were significantly larger in the High-pain group than those in the Control group. This effect was mediated by self-reported fear, but not by fear-potentiated startle. Groups did not differ in the extinction rate. However, only the High-pain group maintained significant nocebo responses at the end of extinction. Anticipatory pain-related fear induced through a threat manipulation did not amplify nocebo hyperalgesia. These findings suggest that fear of high pain may be a key contributor to the amplification of nocebo hyperalgesia, only when high pain is experienced and not when it is merely anticipated.

Abstract
Common practice during local anesthetic injection is to warn the patient using words such as: "You will feel a big bee sting; this is the worst part." Our hypothesis was that using gentler words for administration of the local anesthetic improves pain perception and patient comfort. One hundred forty healthy women at term gestation requesting neuraxial analgesia were randomized to either a "placebo" ("We are going to give you a local anesthetic that will numb the area and you will be comfortable during the procedure") or "nocebo" ("You are going to feel a big bee sting; this is the worst part of the procedure") group. Pain was assessed immediately after the local anesthetic skin injection using verbal analog scale scores of 0 to 10. Median verbal analog scale pain scores were lower when reassuring words were used compared with the harsher nocebo words (3 [2-4] vs 5 [3-6]; P < 0.001). Our data suggest that using gentler, more reassuring words improves the subjective experience during invasive procedures.

Abstract
We present an fMRI study demonstrating that an onomatopoeia word highly suggestive of subjective pain, heard by the ear, significantly activates the anterior cingulate cortex (ACC) while hearing non-sense words that did not imply affective pain under the same task does not activate this area in humans. We concluded that the ACC would be a pivotal locus for perceiving affective pain evoked by an onomatopoeia word that implied affective pain closely associated with the unpleasantness of pain. We suggest that the pain affect sustained by pain unpleasantness may depend on ACC-prefrontal cortical interactions that modify cognitive evaluation of emotions associated with word-induced pain.

Abstract
This study aimed to identify electrophysiological correlates of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) has been found to impact how healthy and patient populations experience pain and is a phenomenon that could be better understood in terms of its neurophysiological underpinnings. In this study, nocebo hyperalgesia was induced in 36 healthy participants through classical conditioning and negative suggestions. Electroencephalography was recorded during rest (pre- and post-acquisition) and during pain stimulation (baseline, acquisition, evocation) First, participants received baseline high thermal pain stimulations. During nocebo acquisition, participants learned to associate an inert gel applied to their forearm with administered high pain stimuli, relative to moderate intensity control stimuli administered without gel. During evocation, all stimuli were accompanied by moderate pain, to measure nocebo responses to the inert gel. Pre- to post-acquisition beta-band alterations in long-range temporal correlations (LRTC) were negatively associated with nocebo magnitudes. Individuals with strong resting LRTC showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. These findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing.

Abstract
In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients who gave informed consent to increase their pain for 30 min received a substance known to be non-hyperalgesic (saline solution) and were told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety, we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety.

Abstract
Despite the increasing research on placebos in recent times, little is known about the nocebo effect, a phenomenon that is opposite to the placebo effect and whereby expectations of symptom worsening play a crucial role. By studying experimental ischemic arm pain in healthy volunteers and by using a neuropharmacological approach, we found that verbally induced nocebo hyperalgesia was associated to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of adrenocorticotropic hormone and cortisol plasma concentrations. Both nocebo hyperalgesia and HPA hyperactivity were antagonized by the benzodiazepine diazepam, suggesting that anxiety played a major role in these effects. The administration of the mixed cholecystokinin (CCK) type-A/B receptor antagonist proglumide blocked nocebo hyperalgesia completely but had no effect on HPA hyperactivity, which suggests a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect. Importantly, both diazepam and proglumide did not show analgesic properties on basal pain, because they acted only on the nocebo-induced pain increase. These data indicate a close relationship between anxiety and nocebo hyperalgesia, in which the CCKergic systems play a key role in anxiety-induced hyperalgesia. These results, together with previous findings showing that placebo analgesia is mediated by endogenous opioids, suggest that the analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.

Abstract
Classical theories suggest placebo analgesia and nocebo hyperalgesia are based on expectation and conditioned experience. Whereas the neural mechanism of how expectation modulates placebo and nocebo effects during pain anticipation have been extensively studied, little is known about how experience may change brain networks to produce placebo and nocebo responses. We investigated the neural pathways of direct and observational conditioning for conscious and nonconscious conditioned placebo/nocebo effects using magnetoencephalography and a face visual cue conditioning model. We found that both direct and observational conditioning produced conscious conditioned placebo and nocebo effects and a nonconscious conditioned nocebo effect. Alpha band brain connectivity changes before and after conditioning could predict the magnitude of conditioned placebo and nocebo effects. Particularly, the connectivity between the rostral anterior cingulate cortex and middle temporal gyrus was an important indicator for the manipulation of placebo and nocebo effects. Our study suggests that conditioning can mediate our pain experience by encoding experience and modulating brain networks.

Abstract
Context: Placebo and nocebo effects, the therapeutic and adverse effects, respectively, of inert substances or sham procedures, represent serious confounds in the evaluation of therapeutic interventions. They are also an example of cognitive processes, particularly expectations, capable of influencing physiology.

Objective: To examine the contribution of 2 different neurotransmitters, the endogenous opioid and the dopaminergic (DA) systems, to the development of placebo and nocebo effects.

Design and setting: Using a within-subject design, subjects twice underwent a 20-minute standardized pain challenge, in the absence and presence of a placebo with expected analgesic properties. Studies were conducted in a university hospital setting.

Participants: Twenty healthy men and women aged 20 to 30 years recruited by advertisement.

Main outcome measures: Activation of DA and opioid neurotransmission by a pain stressor with and without placebo (changes in the binding potential of carbon 11 [11C]-labeled raclopride and [11C] carfentanil with positron emission tomography) and ratings of pain, affective state, and anticipation and perception of analgesia.

Results: Placebo-induced activation of opioid neurotransmission was detected in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Regional DA and opioid activity were associated with the anticipated and subjectively perceived effectiveness of the placebo and reductions in continuous pain ratings. High placebo responses were associated with greater DA and opioid activity in the nucleus accumbens. Nocebo responses were associated with a deactivation of DA and opioid release. Nucleus accumbens DA release accounted for 25% of the variance in placebo analgesic effects.

Conclusions: Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

Abstract
Despite the clinical relevance of nocebo effects, few studies have addressed their underlying neural mechanisms in clinically-relevant pain models. We aimed to address the contribution of nocebo effects and their underlying neural circuitry to central pain amplification in visceral pain, as it may develop over repeated painful experiences due to negative pain-related expectations. Healthy volunteers received verbal suggestions of pain sensitization (nocebo group, N=28) or neutral instructions (control group, N=16). fMRI was used to investigate changes in neural responses during cued pain anticipation and painful rectal distensions delivered in successive fMRI sessions. Pain intensity was rated trial-by-trial, and expected pain intensity, state anxiety and tension were assessed prior to each session. Behavioral analyses demonstrated significantly greater increases in both expected and perceived pain in the nocebo group. The fMRI analysis performed on nocebo-responders only (N=14) revealed that these behavioral changes were associated with increased activation within the secondary somatosensory cortex and amygdala during pain anticipation and within the thalamus, insula and amygdala during painful stimulation when compared to controls. A subsequent psycho-physiological interaction analysis of the pain phase showed increased functional connectivity between the anterior insula, which was set-up as seed region based on group results, and midcingulate cortex as a function of negative expectations. These findings support that negative pain-related expectations can play a crucial role in pain amplification of visceral pain, which is mediated, at least in part, by a neural up-regulation of pain-associated areas and their connectivity. These findings may have implications for the pathophysiology and treatment of chronic abdominal pain.

Abstract
Previous studies suggest that nocebo effects, sometimes termed "negative placebo effects," can contribute appreciably to a variety of medical symptoms and adverse events in clinical trials and medical care. In this study, using a within-subject design, we combined functional magnetic resonance imaging (fMRI) and an expectation/conditioning manipulation model to investigate the neural substrates of nocebo hyperalgesia using heat pain on the right forearm. Thirteen subjects completed the study. Results showed that, after administering inert treatment, subjective pain intensity ratings increased significantly more on nocebo regions compared with the control regions in which no expectancy/conditioning manipulation was performed. fMRI analysis of hyperalgesic nocebo responses to identical calibrated noxious stimuli showed signal increases in brain regions including bilateral dorsal anterior cingulate cortex (ACC), insula, superior temporal gyrus; left frontal and parietal operculum, medial frontal gyrus, orbital prefrontal cortex, superior parietal lobule, and hippocampus; right claustrum/putamen, lateral prefrontal gyrus, and middle temporal gyrus. Functional connectivity analysis of spontaneous resting-state fMRI data from the same cohort of subjects showed a correlation between two seed regions (left frontal operculum and hippocampus) and pain network including bilateral insula, operculum, ACC, and left S1/M1. In conclusion, we found evidence that nocebo hyperalgesia may be predominantly produced through an affective-cognitive pain pathway (medial pain system), and the left hippocampus may play an important role in this process.

Abstract
Changes in EEG activity have been related to clinical and experimental pain. Expectation of a negative outcome can lead to pain enhancement (nocebo hyperalgesia) and can alter the response to therapeutic interventions. The present study characterizes EEG alteration related to pain facilitation by nocebo. Thirty healthy subjects were randomly assigned to the nocebo or control group. Five-minute EEG was recorded under: resting state, tonic innocuous heat and tonic noxious heat before and after the application of a sham inert cream to the non-dominant volar forearm combined with cognitive manipulation. The intensity and unpleasantness of heat-induced pain increased after cognitive manipulation in the nocebo group compared to control and was associated with enhanced low alpha (8-10Hz) activity. However, changes in alpha activity were predicted by catastrophizing but not by pain intensity or unpleasantness, which suggest that low alpha power might reflect brain activity related to negative cognitive-affective responses to pain.

Abstract
Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.

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