How Instructions, Learning, and Expectations Shape Pain and Neurobiological Responses.

Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.

[Placebo effects in analgesia : Influence of expectations on the efficacy and tolerability of analgesic treatment]. / Placeboeffekte in der Schmerztherapie : Einfluss der Erwartung auf die Wirksamkeit und Verträglichkeit schmerzmedizinischer Behandlungen.

Expectations of patients influence the perception and neuronal processing of acute and chronic pain and modulate the effectiveness of analgesic treatment. The expectation of treatment is not only the most important determinant of placebo analgesia. Expectations of treatment also influence the efficacy and tolerability of "active" pharmacological and non-pharmacological treatment of pain. Recent insights into the psychological and neurobiological mechanisms underlying the clinically relevant effects of treatment expectations enable and call for the systematic integration and modulation of treatment expectations into analgesic treatment concepts. Such a strategy promises to optimize analgesic treatment and to prevent or reduce the burden of unwanted side effects and the misuse of analgesics, particularly of opioids. This review highlights the current concepts, recent achievements and also challenges and key open research questions.

Experience with opioids does not modify the brain network involved in expectations of placebo analgesia.

Placebo analgesia (PA) is defined as a psychobiological phenomenon triggered by the information surrounding an analgesic drug instead of its inherent pharmacological properties. PA is hypothesized to be formed through either verbal suggestions or conditioning. The present study aims at disentangling the neural correlates of expectations effects with or without conditioning through prior experience using the model of PA. We addressed this question by recruiting two groups of individuals holding comparable verbally-induced expectations regarding morphine analgesia but either (i) with or (ii) without prior experience with opioids. We then contrasted the two groups' neurocognitive response to acute heat-pain induction following the injection of sham morphine using electroencephalography (EEG). Topographic ERP analyses of the N2 and P2 pain evoked potential components allowed to test the hypothesis that PA involves distinct neural networks when induced by expectations with or without prior experience. First, we confirmed that the two groups showed corresponding expectations of morphine analgesia (Hedges' gs < .4 positive control criteria, gs = .37 observed difference), and that our intervention induced a medium-sized PA (Hedges' gav ≥ .5 positive control, gav = .6 observed PA). We then tested our hypothesis on the recruitment of different PA-associated brain networks in individuals with versus without prior experience with opioids and found no evidence for a topographic N2 and P2 ERP components difference between the two groups. Our results thus suggest that in the presence of verbally-induced expectations, modifications in the PA-associated brain activity by conditioning are either absent or very small.

[Neurobiological and neurochemical mechanisms of placebo analgesia]. / Neurobiologische und neurochemische Mechanismen der Placeboanalgesie.

BACKGROUND: The efficacy of pain therapies can be substantially modulated by treatment expectations, which is reflected by the substantial placebo effects observed in pain (so called placebo analgesia). QUESTION: What is currently known about the neurobiological and neurochemical mechanisms underlying placebo analgesia? MATERIALS AND METHODS: A focused presentation of key publications in the field embedded in a structured overview of the mechanistic concepts and current theories according to recent evidence. RESULTS: Experimental studies with functional neuroimaging showed that the effect of placebo analgesia is reflected by changes in brain activity related to pain processing and cognitive control. The important neurotransmitters involved include opioids and dopamine. CONCLUSION: Placebo analgesia is associated with complex neurobiological and -physiological mechanisms. An advanced comprehension of these processes should be applied to optimize existing and future therapeutic approaches in pain therapy.

Parallel cortical-brainstem pathways to attentional analgesia.

Pain demands attention, yet pain can be reduced by focusing attention elsewhere. The neural processes involved in this robust psychophysical phenomenon, attentional analgesia, are still being defined. Our previous fMRI study linked activity in the brainstem triad of locus coeruleus (LC), rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) with attentional analgesia. Here we identify and model the functional interactions between these regions and the cortex in healthy human subjects (n = 57), who received painful thermal stimuli whilst simultaneously performing a visual attention task. RVM activity encoded pain intensity while contralateral LC activity correlated with attentional analgesia. Psycho-Physiological Interaction analysis and Dynamic Causal Modelling identified two parallel paths between forebrain and brainstem. These connections are modulated by attentional demand: a bidirectional anterior cingulate cortex (ACC) - right-LC loop, and a top-down influence of task on ACC-PAG-RVM. By recruiting discrete brainstem circuits, the ACC is able to modulate nociceptive input to reduce pain in situations of conflicting attentional demand.

Investigation of Correlations Between Pain Modulation Paradigms.

OBJECTIVE: Endogenous pain modulation can be quantified through the use of various paradigms. Commonly used paradigms include conditioned pain modulation (CPM), offset analgesia (OA), spatial summation of pain (SSP), and temporal summation of pain (TSP), which reflect spatial and temporal aspects of pro- and antinociceptive processing. Although these paradigms are regularly used and are of high clinical relevance, the underlying physiological mechanisms are not fully understood. DESIGN: The aim of this study is therefore to assess the association between these paradigms by using comparable protocols and methodological approaches. SETTING: University campus. SUBJECTS: Healthy and pain-free volunteers (n = 48) underwent psychophysical assessment of CPM, OA, SSP, and TSP (random order) at the same body area (volar nondominant forearm) with individualized noxious stimuli. METHODS: CPM included heat stimuli before, during, and after a noxious cold-water bath, whereas for OA, three heat stimuli were applied: baseline trial, offset trial, and constant trial. For the SSP paradigm, two differently sized heat stimulation areas were evaluated, whereas for TSP, the first and last stimulus of 10 consecutive short heat stimuli were assessed. A computerized visual analog scale was used to continuously evaluate pain intensity. The magnitudes of all associations between all paradigm pairs were analyzed with Spearman's correlation, and individual influencing factors were assessed with a multivariate linear regression model. RESULTS: Weak to moderate correlations among all four paradigms were found (P > 0.05), and no distinct influencing factors were identified. CONCLUSIONS: A limited association between pain modulation paradigms suggests that CPM, OA, SSP, and TSP assess distinct aspects of endogenous analgesia with different underlying physiological mechanisms.

Merely Possessing a Placebo Analgesic Improves Analgesia Similar to Using the Placebo Analgesic.

BACKGROUND: Placebo analgesia studies generally reported that the actual use of a placebo analgesic reduces pain. Yeung, Geers, and Kam found that the mere possession (without use) of a placebo analgesic also reduces pain. PURPOSE: We investigated the relative effectiveness of using versus possessing a placebo analgesic on pain outcomes. METHODS: In Study 1a, 120 healthy adults were randomized to either the experimental (EXP) conditions (EXP1: used a placebo analgesic cream, EXP2: possessed a placebo analgesic cream) or control (CO) conditions (CO1: possessed a sham cream, CO2: no cream). All participants underwent a cold pressor test (CPT). Study 1b further delineated the effect of possession from the effect of use. Sixty healthy adults were randomized to either the placebo-possession condition (merely possessed a placebo analgesic cream) or the placebo-possession-use condition (possessed and used a placebo analgesic cream). All participants did a CPT. RESULTS: In Study 1a, as expected, a placebo effect was found-participants who used a placebo analgesic cream showed better pain outcomes than the two CO groups. Surprisingly, participants who merely possessed a placebo analgesic cream performed equally well as those who actually used it. In Study 1b, participants in the two conditions did not differ in most pain outcomes. Participants who possessed and used a placebo analgesic cream only showed slightly more reduction in pain intensity compared to participants who merely possessed the placebo analgesic cream. CONCLUSIONS: Our results suggest that merely possessing a placebo analgesic could enhance pain outcomes similar to that of applying the placebo analgesic.

Pain and stress: functional evidence that supra-spinal mechanisms involved in pain-induced analgesia mediate stress-induced analgesia.

Analgesia induced by stressful and painful stimuli is an adaptive response during life-threatening situations. There is no evidence linking the mechanisms underlying them, while the former depends on the activation of stress-related brain pathways, the second depends on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. In this study, we hypothesized that stress-induced analgesia is also dependent on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. We used immobilization, a classical procedure to induce acute stress, and evaluated its ability to decrease the nociceptive responses induced either by carrageenan or by formalin in rats. Immobilization stress significantly decreased either carrageenan-induced hyperalgesia or formalin-induced tonic nociception in a time-dependent manner. This stress-induced analgesia is similar to pain-induced analgesia, as revealed by contrasting the antinociceptive effect induced by immobilization and by a forepaw injection of capsaicin. The administration of a µ-opioid receptor antagonist (CTOP, 0.5 µg) into the nucleus accumbens, as well as that of a nicotinic cholinergic receptor antagonist (mecamylamine, 0.6 µg) into the rostral ventromedial medulla, blocked immobilization stress-induced analgesia in both pain models. These results demonstrate that supraspinal mechanisms which are known to mediate pain-induced analgesia also mediate stress-induced analgesia. Therefore both forms of analgesia have overlapping mechanisms, probably recruited in response to the perception of danger.

Peripherally acting opioid analgesics and peripherally-induced analgesia.

The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities.

Personality Differences of Brain Networks in Placebo Analgesia and Nocebo Hyperalgesia: A Psychophysiological Interaction (PPI) Approach in fMRI.

It is generally believed that the placebo response can elicit an analgesic effect, whilst the nocebo response can elicit a hyperalgesia effect in pain. Placebo analgesia and nocebo hyperalgesia effects are increasing concerns for researchers. Growing evidence suggests personality differences have an impact on both placebo and nocebo effects. However, previous studies have not reached a unified conclusion. We designed this study to explore the personality differences of functional magnetic resonance imaging (fMRI) signals in placebo response and nocebo response by using psychophysiological interaction (PPI) analysis. 30 healthy subjects underwent conditioning induction training to establish expectations of placebo effect and nocebo effect, and then, all subjects completed the following experimental procedures: (1) baseline scanning, (2) acute pain model establishment, (3) pain status scanning, and (4) pseudorandom scanning of block design of placebo response or nocebo response. Behavioral data were collected after each scan. The results of this study showed that (1) there were significant differences of VAS placebo intervention between the extrovert group and the introvert group (p = 0.004); (2) there were significant differences of VAS nocebo intervention between the extrovert group and the introvert group (p = 0.011); (3) there were significant differences between the VAS placebo intervention and VAS pain status (baseline) in both the extrovert group (p < 0.001) and the introvert group (p = 0.001); (4) there were significant differences between the VAS nocebo intervention and VAS pain status (baseline) in both the extrovert group (p = 0.008) and the introvert group (p < 0.001). Moreover, there were significant differences in the brain network for placebo and nocebo responses between different personalities. We found that (1) deactivation differences of the pain-related network and limbic system play an important role in personality differences associated with placebo analgesia and (2) differences of control of anxiety and activation of dorsolateral prefrontal cortex may cause the personality differences observed in nocebo hyperalgesia.

Comparing the Analgesic Effects of 4 Nonpharmacologic Interventions on Term Newborns Undergoing Heel Lance: A Randomized Controlled Trial.

This randomized trial compared the analgesic effect of 4 nonpharmacologic interventions (breastfeeding, oral sucrose, nonnutritive sucking, and skin-to-skin contact) on term newborns between 24 and 48 hours of age who underwent a heel lance. The Neonatal Pain, Agitation, and Sedation Scale was used to evaluate pain. The newborns (N = 226) were assigned to one of 4 intervention groups (n = 176) or a control group without pain intervention (n = 50). The results indicate that all intervention groups showed decreased pain levels when compared with the control group (P < .01). The oral sucrose group experienced a superior analgesic effect when compared with the skin-to-skin contact group (P < .01), but no difference was observed when compared with the breastfeeding group (P > .05) or the nonnutritive sucking group (P > .05). All intervention groups showed a shortened crying time (P < .01) and reduced procedural duration (P < .01) compared with the control group. All of these interventions are clinically applicable and acceptable when caring for a newborn during a minor painful procedure.

Oxytocin enhances the pain-relieving effects of social support in romantic couples.

Social support plays a vital role in physical and mental well-being. The neuropeptide hormone oxytocin (OXT) has been implicated in modulating pair-bonding and affiliative behaviors, but whether OXT contributes to the analgesic effects of a romantic partner's touch remains elusive. In the present randomized placebo-controlled, between-group, functional magnetic resonance imaging study involving 194 healthy volunteers (97 heterosexual couples), we tested the effects of intranasal OXT (24 IU) on handholding as a common mode of expressing emotional support in romantic couples. We scanned the subjects while brief electric shocks were administered. The subjects assumed that they received social support from either their romantic partner or an unfamiliar person. Unbeknown to the subject, in the partner and stranger support conditions, the same male experimenter always held the subject's left hand. Partner support was most effective in reducing the unpleasantness of electric shocks, and OXT further attenuated the unpleasantness across conditions. On the neural level, OXT significantly augmented the beneficial effects of partner support, as evidenced by a stronger decrease of neural responses to shocks in the anterior insula (AI), a stronger activity increase in the middle frontal gyrus (MFG), and a strengthened functional coupling between the AI and MFG. Our results support the notion that OXT specifically modulates the beneficial effects of social support in romantic couples by concomitantly reducing pain-associated activity and increasing activity linked to cognitive control and pain inhibition. We hypothesize that impaired OXT signaling may contribute to the experience of a lack of partner support.

Factors affecting the provision of analgesia during childbirth, Japan.

Japan's universal health-care system means that it is a very safe country in which to give birth. Perinatal outcomes in Japan are excellent, with low infant mortality and neonatal mortality. However, childbirth remains a challenge for many Japanese women, who are faced with a scarcity of places to give birth, limited availability of analgesia and social norms that favour natural birth. The number of birth facilities in Japan continues to decrease as fewer children are born. The numbers of qualified medical staff remain inadequate, with a continuing lack of female physicians, perpetuated by a pervasive negative gender bias. Recruitment efforts are underway, but few doctors want to specialize in obstetrics or gynaecology. Furthermore, around half of female obstetricians and gynaecologists in Japan's male-dominated medical system stop practising when they have their own children. The difficulty of obtaining analgesia during labour is another problem. Although low uptake of labour pain relief in Japan is said to be due to cultural influences, the root of the problem is a lack of qualified anaesthesiologists and the inflexibility of a system that will not allow other staff to be trained to administer labour analgesia. Problems with labour anaesthesia have been linked to 14 maternal deaths since 2010. Japanese policy-makers need to act to renovate the nation's obstetric facilities, reorganize regional perinatal care systems, train more obstetricians and anaesthesiologists, promote task-shifting and better integrate biomedical and traditional, non-medical care for pregnant women.

Le système de soins de santé universel du Japon en fait un pays très sûr pour les accouchements. Les résultats en matière de santé périnatale au Japon sont excellents, avec une mortalité infantile et une mortalité néonatale faibles. Néanmoins, l'accouchement reste problématique pour de nombreuses Japonaises, qui doivent faire face à un manque d'établissements adaptés pour les accouchements, à une disponibilité limitée de l'analgésie et à des normes sociales qui favorisent les accouchements naturels. Le nombre de maternités au Japon ne cesse de baisser, à mesure de la diminution du nombre de naissances. Les effectifs en personnel médical qualifié restent inappropriés, avec une pénurie persistante de femmes médecins, perpétuée par des préjugés négatifs généralisés liés au genre. Des efforts de recrutement sont en cours, mais peu de médecins souhaitent se spécialiser en obstétrique ou en gynécologie. Par ailleurs, dans le système médical japonais dominé par les hommes, près de la moitié des femmes obstétriciennes et gynécologues cessent de pratiquer dès qu'elles ont elles-mêmes des enfants. La difficulté à bénéficier d'une analgésie obstétricale pendant l'accouchement constitue un autre problème. Même si, au Japon, le faible recours au soulagement de la douleur pendant le travail est généralement imputé à des influences culturelles, le fond du problème est une pénurie d'anesthésistes qualifiés et le manque de souplesse d'un système qui ne permet pas de former d'autres professionnels de santé pour pouvoir pratiquer l'analgésie obstétricale. Les problèmes liés à la réalisation d'une analgésie obstétricale ont donné lieu à 14 décès maternels depuis 2010. Au Japon, les décideurs politiques doivent agir pour rénover les installations obstétricales du pays, réorganiser les systèmes régionaux de santé périnatale, former davantage d'obstétriciens et d'anesthésistes, promouvoir le transfert des tâches et mieux intégrer les soins biomédicaux et les soins traditionnels, non médicaux, pour les femmes enceintes.

El sistema universal de atención sanitaria de Japón hace que sea un país muy seguro para dar a luz. Los resultados perinatales en Japón son excelentes, con baja mortalidad infantil y mortalidad neonatal. Sin embargo, el parto sigue siendo un problema para muchas mujeres japonesas, que se enfrentan a la escasez de lugares para dar a luz, la limitada disponibilidad de analgesia y las normas sociales que favorecen el parto natural. El número de centros de maternidad en Japón sigue disminuyendo a medida que nacen menos niños. El número de personal médico cualificado sigue siendo insuficiente, con una continua falta de mujeres médicas, perpetuada por un prejuicio de género negativo generalizado. Los esfuerzos de reclutamiento están en marcha, pero pocos médicos quieren especializarse en obstetricia o ginecología. Además, alrededor de la mitad de las obstetras y ginecólogas del sistema médico japonés dominado por los hombres dejan de ejercer cuando tienen sus propios hijos. La dificultad para obtener analgesia durante el trabajo de parto es otro problema. Aunque se dice que la baja aceptación del alivio del dolor del trabajo de parto en Japón se debe a influencias culturales, la raíz del problema es la falta de anestesiólogos calificados y la inflexibilidad de un sistema que no permitirá que otro personal esté capacitado para administrar la analgesia del trabajo de parto. Los problemas con la anestesia del trabajo de parto se han relacionado con 14 muertes maternas desde 2010. Los responsables de formular políticas en Japón deben actuar para renovar las instalaciones obstétricas del país, reorganizar los sistemas regionales de atención perinatal, capacitar a más obstetras y anestesiólogos, promover el cambio de tareas e integrar mejor la atención biomédica y la atención no médica tradicional para las mujeres embarazadas.

Results after implementation of a sedoanalgesia protocol for procedures in hospital environment. / Resultados tras implantación de un protocolo de sedoanalgesia para procedimientos en ámbito hospitalario.

INTRODUCTION: We analyze the effectiveness and safety of a specific analgosedation protocol for procedures, and eva luate the satisfaction of the health personnel with each procedure. PATIENTS AND METHOD: Prospective study of an analgosedation protocol for hospital procedures in children under 18 years of age, with an individualized strategy based on the patient's baseline situation, the type of procedure and the experience of the pediatrician responsible for the sedation. The following variables were recorded: diagnosis motivating the procedure, type of procedure, anthropometric data, allergies, medication, ASA status and baseline disease, fasting time, lung auscultation, temperature, oxygen saturation, res piratory rate, heart rate, blood pressure, sedation location, type of drug, dose, route of administra tion, Ramsay sedation scale, duration of sedation, type and treatment of adverse effects, presence of family members throughout the procedure, and patient satisfaction. RESULTS: 279 sedations were performed. The most commonly used drugs were nitrous oxide (62.7%) and midazolam (16.5%); the most commonly used routes of administration were the inhaled one (62.4%) and the intravenous one (15.8%). The satisfaction was high for the pediatrician (92.5%), the nurse (94.3%), the family (96.8%), and patients (93.6%), with a good correlation between them, and it was significantly lower when using midazolam and the nasal and oral routes. The adverse effects rate was 3.2%, and none was severe. CONCLUSIONS: The implementation of a specific analgosedation protocol for procedures in the hospital environment achieves high levels of effectiveness and safety, as well as a high level of satisfaction, both in family members and in health personnel.

Frontal-Brainstem Pathways Mediating Placebo Effects on Social Rejection.

Placebo treatments can strongly affect clinical outcomes, but research on how they shape other life experiences and emotional well-being is in its infancy. We used fMRI in humans to examine placebo effects on a particularly impactful life experience, social pain elicited by a recent romantic rejection. We compared these effects with placebo effects on physical (heat) pain, which are thought to depend on pathways connecting prefrontal cortex and periaqueductal gray (PAG). Placebo treatment, compared with control, reduced both social and physical pain, and increased activity in the dorsolateral prefrontal cortex (dlPFC) in both modalities. Placebo further altered the relationship between affect and both dlPFC and PAG activity during social pain, and effects on behavior were mediated by a pathway connecting dlPFC to the PAG, building on recent work implicating opioidergic PAG activity in the regulation of social pain. These findings suggest that placebo treatments reduce emotional distress by altering affective representations in frontal-brainstem systems.SIGNIFICANCE STATEMENT Placebo effects are improvements due to expectations and the socio-medical context in which treatment takes place. Whereas they have been extensively studied in the context of somatic conditions such as pain, much less is known of how treatment expectations shape the emotional experience of other important stressors and life events. Here, we use brain imaging to show that placebo treatment reduces the painful feelings associated with a recent romantic rejection by recruiting a prefrontal-brainstem network and by shifting the relationship between brain activity and affect. Our findings suggest that this brain network may be important for nonspecific treatment effects across a wide range of therapeutic approaches and mental health conditions.

Pain relief provided by an outgroup member enhances analgesia.

Pain feels different in different social contexts, yet the mechanisms behind social pain modulation remain poorly understood. To elucidate the impact of social context on pain processing, we investigated how group membership, one of the most important social context factors, shapes pain relief behaviourally and neurally in humans undergoing functional neuroimaging. Participants repeatedly received pain relief from a member of their own group (ingroup treatment) or a member of a disliked outgroup (outgroup treatment). We observed a decrease in pain ratings and anterior insula (AI) pain responses after outgroup treatment, but not after ingroup treatment. Moreover, path analyses revealed that the outgroup treatment induced a stronger relief learning in the AI, which in turn altered pain processing, in particular if the participant entered the treatment with a negative impression toward the outgroup individual. The finding of enhanced analgesia after outgroup treatment is relevant for intergroup clinical settings. More generally, we found that group membership affects pain responses through neural learning and we thus elucidate one possible mechanism through which social context impacts pain processing.

Enhancing Placebo Effects in Somatic Symptoms Through Oxytocin.

OBJECTIVE: Placebo effects relieve various somatic symptoms, but it is unclear how they can be enhanced to maximize positive treatment outcomes. Oxytocin administration may potentially enhance placebo effects, but few studies have been performed, and they have had conflicting findings. The study aim was to investigate the influence of positive verbal suggestions and oxytocin on treatment expectations and placebo effects for pain and itch. METHODS: One hundred eight female participants were allocated to one of the following four groups: (1) oxytocin with positive verbal suggestions, (2) placebo with positive verbal suggestions, (3) oxytocin without suggestions, and (4) placebo without suggestions. The administration of 24 IU oxytocin or a placebo spray was preceded by positive verbal suggestions regarding the pain- and itch-relieving properties of the spray or no suggestions, depending on group allocation. Pain was assessed with a cold pressor test, and itch was assessed with histamine iontophoresis. RESULTS: Positive verbal suggestions induced expectations of lower pain (F = 4.77, p = .031) and itch (F = 5.38, p = .022). Moreover, positive verbal suggestions elicited placebo analgesia (F = 5.48, p = .021) but did not decrease itch. No effect of oxytocin on the placebo effect or on expectations was found. CONCLUSIONS: Positive suggestions induced placebo analgesia but oxytocin did not enhance the placebo effect. Study limitations are that we only included a female sample and a failure to induce placebo effect for itch. Future studies should focus on how oxytocin might influence placebo effects, taken into account the role of sex, dose-dependent effects, and various expectation manipulations. TRIAL REGISTRATION: The study was registered as a clinical trial on www.trialregister.nl (number 6376).

How Classical Conditioning Shapes Placebo Analgesia: Hidden versus Open Conditioning.

Objective: To investigate the influence of expectancy of pain intensity, fear of pain (trait), and fear (state) on the effectiveness of hidden and open conditioning to produce placebo analgesia. Methods: A total of 90 healthy female volunteers were randomly assigned to three groups (hidden conditioning, open conditioning, and control) that received electrical stimuli preceded by either orange or blue lights. One color was paired with painful stimuli (control stimuli) and the other color was paired with nonpainful stimuli (conditioned stimuli) in both the hidden and open conditioning groups. Only participants in the open conditioning group were informed about this association. In the control group, both color lights were followed by control stimuli. In the testing phase, both colored lights were followed by identical control stimuli. Participants rated pain intensity, expectancy of pain intensity, fear, and fear of pain. Results: A significant analgesic effect was found only in the hidden conditioning group, where no explicit verbal suggestions were provided. Hidden conditioning had an effect on expectancy and fear-participants in the hidden conditioning group expected less pain and experienced less fear in relation to conditioned stimuli. Fear was the only predictor of placebo analgesia in the hidden conditioning group. Neither expectancy of pain intensity nor fear of pain predicted placebo analgesia. Conclusions: Fear seems to be a more important factor than expectancy in producing placebo analgesia induced by hidden conditioning.

High-risk respiratory patients' experiences of bronchoscopy with conscious sedation and analgesia: A qualitative study.

AIMS AND OBJECTIVES: To understand the experiences of high-risk respiratory patients undergoing bronchoscopy with conscious sedation. BACKGROUND: Due to possible complications, high-risk respiratory patients are usually given smaller, cautious doses of sedation and analgesia for bronchoscopy. Described as "conscious sedation," this facilitates depression of the patient's consciousness without causing respiratory compromise. Previously, studies have investigated patient experience using quantitative methods. This is the first study that has explored the patient experience during bronchoscopy from a qualitative perspective. DESIGN: Qualitative, phenomenological approach as described by Van Manen. METHODS: The setting was an endoscopy unit within an Australian tertiary hospital. Unstructured interviews were conducted with 13 patients with chronic obstructive pulmonary disease who underwent day-case bronchoscopy. All participants received conscious sedation. They were interviewed twice, within a week, postprocedure. Interviews were transcribed verbatim and analysed using Van Manen's interpretive approach. FINDINGS: Participants had varying experiences. Five themes emerged from the analysis: Frustration and fear; Comfort and safety; Choking and coughing; Being aware; and Consequences. Whilst not all participants experienced procedural awareness or remembered it, for those who did it was a significant event. Overall, experiences were found to be negative; however, participants accepted and tolerated them, perceiving them as necessary to obtain a diagnostic result. CONCLUSION: The findings demonstrate that often patients are aware during the procedure and their experience may be uncomfortable and distressing. RELEVANCE TO CLINICAL PRACTICE: These findings have implications for patient preparation pre- and post-bronchoscopy in terms of what they might expect, and to discuss what has happened after the procedure. Some practices of the bronchoscopy team during the procedure may need modification. For example, in anticipation of the possibility that the patient may be aware, healthcare professionals should provide patient-focused explanations of what is happening during the procedure, as well as providing ongoing reassurance that everything is going as planned.

The Placebo Analgesic Effect in Healthy Individuals and Patients: A Meta-Analysis.

OBJECTIVE: The present meta-analysis investigates whether the magnitude of placebo analgesia is different in patients compared with healthy individuals and whether placebo analgesia is different in experimentally induced pain compared with clinical pain in patients. METHODS: A literature search in Web of Science (ISI) on the terms "placebo analgesia" and "placebo analgesic" was conducted. The search resulted in 71 studies, including 4239 participants. Fifty-five studies included healthy individuals and 16 studies included patients. Of the 16 studies with patients, five studies investigated clinical pain and 11 studies investigated experimentally induced pain. RESULTS: The average effect size was 1.24 for healthy individuals and 1.49 for patients. In the studies with patients, the average effect sizes of placebo treatment were 1.73 for experimentally induced pain and 1.05 for clinical pain. A χ test revealed that there were relatively more studies with patients compared with healthy volunteers in which there was a clinically significant reduction in pain (p = .040). CONCLUSIONS: The findings suggest that patients benefited from placebo treatment to a greater degree than healthy individuals did and that studies on healthy individuals may underestimate the magnitude of the placebo analgesic effect in patients. Patients' clinical pain and experimentally induced pain respond to placebo to the same degree.