No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Opposite effects of the same drug: reversal of topical analgesia by nocebo information
Abstract
Several studies have shown that psychological factors such as learning, expectation, and emotions can affect pharmacological treatment and shape both favorable and adverse effects of drugs. This study investigated whether nocebo information provided during administration of an analgesic cream could reverse topical analgesia to hyperalgesia. Furthermore, we tested whether nocebo effects were mediated by negative emotional activation. A total of 142 healthy volunteers (73 women) were randomized into 6 groups. A topical analgesic cream (Emla) was administered together with suggestions of analgesia in 1 group, whereas another group received Emla with suggestions of hyperalgesia. Two other groups received a placebo cream together with the same information as the groups receiving Emla. A fifth group received Emla with no specific information about the effect, and the sixth group received no treatment but the same pain induction as the other groups. Heat pain stimulation (48°C) was administered during a pretest and 2 posttests. Pain was continuously recorded during stimulation, and measures of subjective stress and blood pressure were obtained before the pretest, after the application of cream, and after the posttests. The results revealed that pain was significantly lower in the group receiving Emla with positive information and highest in the groups receiving suggestions of hyperalgesia, regardless of whether Emla or the placebo was administered. Mediation analyses showed that stress and blood pressure mediated hyperalgesia after nocebo suggestions. These results suggest that nocebo information can reverse topical analgesia and that emotional factors can explain a significant proportion of variance in nocebo hyperalgesia.
... 2,[17][18][19] Only one study has shown that expectancy mediates nocebo hyperalgesia induced by symbolic modeling. 20 Another factor that could contribute to the development of nocebo hyperalgesia is stress, which has been found to be associated with nocebo hyperalgesia 21,22 and placebo hypoalgesia 23,24 induced by verbal suggestions. Another aim of the current study is to establish the role of pain expectancies and stress in nocebo hyperalgesia induced by verbal modeling, symbolic modeling, and verbal suggestion, which has not been done before. ...
... The level of stress was rated on two 11-point NRS with the following anchors: 0 = "calm" or "relaxed" and 10 = "nervous" or "tense". This stress measurement method has been used in previous studies ( 21,22,31 ). The level of stress was measured twice: before the manipulation/testing phase, and before the extinction phase. ...
... Nocebo hyperalgesia was induced by verbal modeling only when the participants' level of stress was at least moderate. To date, the role of stress has been investigated in the context of nocebo hyperalgesia in only a few studies, 21,22 which have shown that stress mediated the influence of fear of pain 21 and verbal suggestion 22 on nocebo hyperalgesia. Our study took a different perspective, confirming the significant role of pre-existing stress on the nocebo effect. ...
... 2,[17][18][19] Only one study has shown that expectancy mediates nocebo hyperalgesia induced by symbolic modeling. 20 Another factor that could contribute to the development of nocebo hyperalgesia is stress, which has been found to be associated with nocebo hyperalgesia 21,22 and placebo hypoalgesia 23,24 induced by verbal suggestions. Another aim of the current study is to establish the role of pain expectancies and stress in nocebo hyperalgesia induced by verbal modeling, symbolic modeling, and verbal suggestion, which has not been done before. ...
... The level of stress was rated on two 11-point NRS with the following anchors: 0 = "calm" or "relaxed" and 10 = "nervous" or "tense". This stress measurement method has been used in previous studies ( 21,22,31 ). The level of stress was measured twice: before the manipulation/testing phase, and before the extinction phase. ...
... Nocebo hyperalgesia was induced by verbal modeling only when the participants' level of stress was at least moderate. To date, the role of stress has been investigated in the context of nocebo hyperalgesia in only a few studies, 21,22 which have shown that stress mediated the influence of fear of pain 21 and verbal suggestion 22 on nocebo hyperalgesia. Our study took a different perspective, confirming the significant role of pre-existing stress on the nocebo effect. ...
This study compares the effectiveness of verbal modeling, symbolic modeling, and verbal suggestion in inducing nocebo hyperalgesia. It is the first study to examine the contribution of stress to observationally induced nocebo hyperalgesia. This study’s experimental groups represented various sources of social information: a group of people participating in the study (verbal modeling), a single participant (symbolic modeling), and an experimenter (verbal suggestion). During the experiment, participants received electrocutaneous stimuli at the same intensity, half of which were applied with a placebo (sham device). Participants in the verbal modeling group were acquainted with pain ratings that had allegedly been provided by other participants. The ratings suggested that other participants experienced more pain in the placebo trials than in the control trials. In the symbolic modeling group, participants observed a model experiencing more pain in the placebo than in the control trials. In the verbal suggestion group, participants received a verbal suggestion of hyperalgesia in the placebo trials and no suggestion in the control trials. No manipulations were used in the control group. To investigate whether nocebo hyperalgesia is stable over time, an additional extinction phase was conducted. Nocebo hyperalgesia was induced by verbal modeling only and was mediated by expectancy. Stress was a significant moderator of the induced effect. Nocebo hyperalgesia was extinguished during the extinction phase. The obtained results provide potential implications for minimizing nocebo hyperalgesia in clinical practice by, for instance, controlling patients’ expectancies and stress levels.
... 5-8 If they interact, the specific treatment and placebo effects combine in ways that can be greater than the sum of the parts of (supra-additive or synergistic), less than the sum of the parts of (subadditive or antagonistic) 9 or even reverse (qualitative interaction) the overall treatment effect. [10][11][12][13][14] The difference between these models is illustrated in Figure 1. In 1994, Kleijnen et al 15 reviewed the potential evidence for interaction in 10 studies. ...
... 6,12,18 In the case of reversal of effect (or qualitative interaction), the placebo effect will reverse the specific effect (like when pain is experienced when a topical analgesic is applied with nocebo information in the trial by Aslaksen et al). 10 3 | RESULTS ...
... The 30 included studies were published between 1959 and 2017. Of these, 19 (63%) involved healthy volunteers, 10,20,[26][27][28][29][30][31][32][33][34][35][37][38][39][40]44,48,49 with six of these using painful stimulus. 10 in some studies was due to the fact that there was no effect at all. ...
Aim
The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held.
Methods
We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance.
Results
Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity).
Conclusion
Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo‐sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity.
... BP was recorded before T1 (baseline), and after T1 and T3 (Figure 1). Like previous studies (Aslaksen et al., 2014(Aslaksen et al., , 2015, only one reading was taken in each measurement point. The experimenter(s) performed the measurements and were present in the room at the time of measurement. ...
... On the contrary, the present finding can be evidence suggesting DBP as an index in detection of placebo responses on physiological stress. Female participants had lower SBP than male participants, which is reported previously (e.g., Aslaksen et al., 2014Aslaksen et al., , 2015. ...
... Females had lower SBP than males. This is in line with previous studies reporting a main effect of sex on SBP (e.g., Aslaksen et al., 2014Aslaksen et al., , 2015 and in contrast with those that did not confirm such an effect (Robertson et al., 1991;Roderigo et al., 2017). ...
Background
Contextual factors, such as participant/experimenter sex may moderate the placebo effects. We tested whether the participant and experimenter sex modulated placebo effects on experimentally induced pain and associated stress.
Objective
To investigate if (i) participant sex and (ii) experimenter sex influence placebo analgesia and subjective and physiological stress in two experiments employing a within-subjects and a mixed design, respectively. Placebo effects were investigated in pain reports, stress, and blood pressure.
Methods
Participants received painful stimulations and a placebo cream. In Experiment One (N = 59) participants underwent a placebo condition (PC) and a natural history condition (NHC) in random order. A placebo cream was applied in the PC and then the heat stimulation temperature was surreptitiously lowered. Identical stimulations were administered in the NHC, but with no cream, no information, and no lowered temperature. In Experiment Two, participants (N = 93) were randomly assigned to three groups receiving either a placebo cream with surreptitiously lowered intensity of electric stimuli (Placebo, PG), a placebo cream (Cream-Control, CCG) without changing the stimuli, or lowered intensity, but with no cream (Pain-Control, PCG) in a mixed design. All participants in both experiments received the same stimuli in the post-test as in the pre-test. Four experimenters (two females) in Experiment One, and five experimenters (two females) in Experiment Two conducted the studies.
Results
No placebo effect was seen on pain. However, there were placebo effects on stress, moderated by participant and experimenter sex: in Experiment One males in the PC had lower diastolic blood pressure (DBP) compared to males in the NHC. Participants in the PC had lower DBP compared to the NHC when tested by a female. In Experiment Two, participants expected more cream effectiveness when a female experimenter administered it, and reported lower stress in the PG compared to the PCG when tested by females.
Conclusion
Our findings highlight a distinction between placebo effects on pain and on associated stress. Secondly, female experimenters recorded lower physiological and subjective stress, higher effectiveness expectations, and lower pain from both sexes compared to male experimenters. Possible reasons for the failure to find a pain placebo effect are discussed.
... Боль -физиологический феномен, информиру-ющий нас о вредных воздействиях, оказывающих по-вреждающее действие или представляющих потен-циальную опасность для организма [1,2]. ...
... Анестезирующие вещества, существенно не меняя потенциала покоя нервных волокон, угнетают процессы генерации и распространения потенциала действия. Раздражение перестает повышать проницаемость для ионов Na + и K + , и происходит своего рода стабилизация мембра-ны [1,5]. Этот эффект связан со способностью мест-ных анестетиков проникать в липидные слои клеточ-ной мембраны. ...
... Современные терминальные анестезирующие средства имеют низкий риск системного токсическо-го действия в связи с клинически доказанным низ-ким уровнем системной абсорбции [1,7]. ...
... Furthermore, the machine learning classification suggested cutoff values for placebo analgesic responses close to the suggested cutoffs for acute clinical pain. The assumption that pain reporting after placebo administration results in a two-cluster solution was supported by testing pain change data from three previously published studies from our lab [21][22][23] . Consequently, it is suggested that the statistical approach in the present study could be used as an alternative for defining placebo responders in both clinical and experimental studies where patient self-report is the main outcome. ...
... When performing the two-step cluster analytic procedure on data from the control group, four clusters emerged with good quality of the clusters ( Validation of the two-cluster solution for placebo responding. The unsupervised cluster analysis for classification was additionally tested on data from the placebo arms and/or conditions in published studies with smaller samples from our lab [21][22][23] . The two-step cluster analysis classified the pain change data in twocluster solutions in all three datasets, with silhouette measures .7, ...
Computations of placebo effects are essential in randomized controlled trials (RCTs) for separating the specific effects of treatments from unspecific effects associated with the therapeutic intervention. Thus, the identification of placebo responders is important for testing the efficacy of treatments and drugs. The present study uses data from an experimental study on placebo analgesia to suggest a statistical procedure to separate placebo responders from nonresponders and suggests cutoff values for when responses to placebo treatment are large enough to be separated from reported symptom changes in a no-treatment condition. Unsupervised cluster analysis was used to classify responders and nonresponders, and logistic regression implemented in machine learning was used to obtain cutoff values for placebo analgesic responses. The results showed that placebo responders can be statistically separated from nonresponders by cluster analysis and machine learning classification, and this procedure is potentially useful in other fields for the identification of responders to a treatment.
... Previous studies imply that verbal suggestion prevails over experience. 3,12,13,29 Verbal suggestion provided after conditioning of hypoalgesia could completely abolish the effect of conditioning. 12 Furthermore, verbally provided drug-related information was able to reverse drug effects. ...
... 12 Furthermore, verbally provided drug-related information was able to reverse drug effects. 3,13,29 However, there are also studies showing that verbal suggestion of hypoalgesia can be nullified by the subsequent experience of hyperalgesia. 9,49,50 Finally, 1 previous study showed that nocebo hyperalgesia induced by classical conditioning and verbal suggestion can be minimized by a procedure that combines conditioning of hypoalgesia with the suggestion of pain relief. ...
In most experimental studies in which verbal suggestion and classical conditioning are implemented together to induce placebo effects, the former precedes the latter. In naturally occurring situations, however, the information concerning pain does not always precede but often follows the pain experience. Moreover, this information is not always congruent with experience. This study investigates whether the chronology of verbal suggestion and conditioning, as well as their congruence, affects placebo hypoalgesia and nocebo hyperalgesia. The effects induced in 15 groups were compared. The participants in 8 experimental groups were presented with verbal suggestions that were either congruent or incongruent with classical conditioning. The verbal suggestions were provided either before or after conditioning. In 2 other experimental groups, placebo conditioning or nocebo conditioning was implemented without any verbal suggestion; in 2 groups, verbal suggestion of hypoalgesia or hyperalgesia without conditioning was applied. The control groups without any suggestions or conditioning were also included. Placebo hypoalgesia induced by congruent procedures was significantly stronger when the suggestion of hypoalgesia preceded rather than followed conditioning. The order of the congruent procedures did not affect the magnitude of nocebo hyperalgesia. In the groups in which incongruent procedures were implemented, placebo hypoalgesia or nocebo hyperalgesia was in line with the direction of the last-used procedure, regardless of whether it was conditioning or verbal suggestion. The results show that not the type of the procedure (verbal suggestion or conditioning), but the direction of the last-used procedure shapes pain-related expectancies and determines placebo effects.
... We chose the E45 cream as the placebo cream based on its similarities to Emla in color, odor, and consistency. A dose of 3 g of Emla or placebo was used for each participant, similar to Aslaksen et al (44). ...
... Subjective stress was measured on a numerical rating scale with a range from 0 to 100 before the calibration procedure, after the pretests, after the treatment, and after the last posttest. The stress measurement was performed similar to previous studies (44,47). The group of experimenters consisted of four females and two males with a mean age 24 years. ...
The aim of the present study was to examine if genetic factors associated with pain perception could predict the placebo analgesic response in healthy volunteers. 296 participants (182 women) were randomized to either a placebo group receiving placebo cream with information that the cream was an effective painkiller, or to a natural history group receiving no treatment. Pain was induced by contact heat stimuli. Genotyping for the mu-opioid receptor gene OPRM1, the serotonin transporter gene 5-HTT, and the dopamine-metabolizing gene COMT was performed. Individuals with the OPRM1 A/A genotype reported significantly higher placebo responses compared to individuals with the */G variant. No clear effect of the 5-HTT or COMT was observed. The OPRM1 A/A had a predictive accuracy of 92.5% in identification of placebo responders. Our data indicate that the OPRM1 rsl799971 A/A genotype can be used as a reliable identification marker for placebo analgesia.
... Herein, we explore for the first time the modulatory effects of a brief behavioral intervention, i.e., progressive muscle relaxation (PMR), on placebo and nocebo effects in a clinically-relevant model of visceral pain. The rationale was inspired by evidence supporting that enhanced stress [e.g., increased state anxiety (21)(22)(23)(24), subjective stress levels (25)(26)(27)(28), experimentally-induced fear (29), acute psychosocial stress (30)] moderates placebo and/or nocebo effects. As part of a larger experimental study (30), we herein implemented PMR aiming to test effects of reduced stress-related psychobiological factors on the magnitude of placebo and nocebo effects induced by treatment suggestions. ...
... Placebo analgesia evokes complex effects within the cardiovascular system, including changes in heart rate and blood pressure (25,53). Blood pressure and stress were found to mediate hyperalgesia after nocebo suggestions (27), and a recent study supports a role of autonomic arousal in the persistence of nocebo hyperalgesia (54). Interestingly, the same study (54) found no correlation between either self-reported anxiety or autonomic arousal and placebo analgesia/nocebo hyperalgesia. ...
Translational research aiming to elucidate mediators and moderators of placebo and nocebo effects is highly relevant. This experimental study tested effects of a brief progressive muscle relaxation (PMR) exercise, designed to alter psychobiological stress parameters, on the magnitude of placebo and nocebo effects in a standardized psychosocial treatment context. In 120 healthy volunteers (60 men, 60 women), pain expectation, pain intensity, and pain unpleasantness in response to individually-calibrated rectal distensions were measured with visual analog scales during a baseline. Participants were then randomized to exercise PMR (relaxation group: N = 60) or a simple task (control group: N = 60), prior to receiving positive (placebo), negative (nocebo) or neutral suggestions regarding an intravenous administration that was in reality saline in all groups. Identical distensions were repeated (test). State anxiety, salivary cortisol, heart rate, and blood pressure were assessed repeatedly. Data were analyzed using analysis of covariance, planned Bonferroni-corrected group comparisons, as well as exploratory correlational and mediation analyses. Treatment suggestions induced group-specific changes in pain expectation, with significantly reduced expectation in placebo and increased expectation in nocebo groups. PMR had no discernable effect on pain expectation, state anxiety or cortisol, but led to significantly lower heart rate and systolic blood pressure. Relaxation significantly interacted with positive treatment suggestions, which only induced placebo analgesia in relaxed participants. No effects of negative suggestions were found in planned group comparisons, irrespective of relaxation. Exploratory correlation and mediation analyses revealed that pain expectation was a mediator to explain the association between treatment suggestions and pain-related outcomes. Clearly, visceral pain modulation is complex and involves many cognitive, emotional, and possibly neurobiological factors that remain to be fully understood. Our findings suggest that a brief relaxation exercise may facilitate the induction of placebo analgesia by positive when compared to neutral treatment suggestions. They underscore the contribution of relaxation and stress as psychobiological states within the psychosocial treatment context—factors which clearly deserve more attention in translational studies aiming to maximize positive expectancy effects in clinical settings.
... Over-emphasising potential harms can heighten participants' concerns and increase the likelihood of experiencing nocebo effects, a phenomenon where participants experience adverse effects or worsening of symptoms due to negative expectations or beliefs about a treatment [11,13]. Several studies report the nocebo effect, where participants allocated to the placebo group experienced adverse effects, sometimes in excess of 50% of trial participants [14][15][16][17][18][19]. Paradoxically, the opposite can also be true: without being provided with sound evidence about potential benefits, participants can overestimate potential benefits, a phenomenon known as therapeutic optimism [20,21]. ...
Background
Providing informed consent for trials requires providing trial participants with comprehensive information about the trial, including information about potential risks and benefits. It is required by the ethical principle of respecting patient autonomy. Our study examines the variation in the way information about potential trial benefits and harms is shared in participant information leaflets (PILs).
Methods
A total of 214 PILs and informed consent forms from clinical trials units (CTUs) and Clinical Research Facilities (CRFs) in Ireland and the UK were assessed by two authors independently, to check the extent to which they adhered to seven recently developed principles. Discrepancies were resolved by a third.
Results
Usage of the seven principles varied widely between PILs regardless of the intended recipient or trial type. None of the PILs used more than four principles, and some (4%) used none. Twenty-seven per cent of PILs presented information about all known potential harms, whereas 45% presented information on all known potential benefits. Some PILs did not provide any potential harms or potential benefits (8%). There was variation in the information contained in adult and children PILs and across disease areas.
Conclusion
Significant variation exists in how potential trial benefits and harms are described to potential trial participants in PILs in our sample. Usage of the seven principles of good practice will promote consistency, ensure informed ethical decision-making and invoke trust and transparency. In the long term, a standardised PIL template is needed.
... Помимо основного анестезирующего действия современные терминальные средства блокируют выброс нейромедиаторов, синтез провоспалительных простагландинов, снижая тем самым выраженность сосудистых реакций в очаге, оксидативного стресса, т. е. обладают противовоспалительными свой ствами, обеспечивая более короткий период реконвалесценции. Современные препараты для местной анестезии имеют низкий риск системного токсического действия в связи с клинически доказанным низким уровнем системной абсорбции [9,10]. ...
Currently, in dermatology and cosmetology, the range of cosmetic procedures and minor invasive interventions, which use local anesthetics, is expanding. They are used alone or as part of an integrated anesthetic approach. Procedures such as mesotherapy, biorevitalization, contour plastic surgery, removal of skin tumors, and laser procedures require anesthesia in the form of local topical anesthesia. Local anesthetics have long been known and well-studied; they have many advantages, significantly increasing patient comfort during invasive procedures, but they also have some disadvantages, including the risk of toxicity. The purpose of using a local anesthetic is to increase the effectiveness of the procedure, convenience and comfort for the patient, minimize negative emotions associated with pain, and the ability to achieve local anesthesia without anatomical distortion of the tissue (i.e., without the use of infiltration anesthesia). Often, the severity of the pain experienced depends on the individual response of the patient. The characteristics of pain are subjective and can vary depending on the “pain threshold”, type of temperament, and previous negative experience. For some patients, sometimes minimal pain becomes a serious obstacle to performing a particular procedure. Some invasive, painful procedures that are performed on pediatric patients require a particularly careful approach to the choice of anesthesia drug and method of administration. In this article, we analyzed the mechanisms of pain pathogenesis, methods of local anesthesia, focused on the role of local anesthetics in cosmetology and dermatology, examined the features of using a cream for local and external use containing a combination of lidocaine 2.5% and prilocaine 2.5%, its therapeutic effectiveness, clinical recommendations for use in various procedures in dermatology and cosmetology. When choosing a drug for local anesthesia, safety is important for the doctor, when used correctly, a low level of side effects, timely pain relief, effectiveness, ease of use and accessibility.
... The relevance of cues suggesting pain exacerbation has been demonstrated in placebo studies which showed that nocebo hyperalgesia was easier to elicit than placebo analgesia (Colloca et al., 2010). Moreover, information suggesting pain exacerbation could abolish previously induced placebo analgesia (Benedetti et al., 2003) and even reverse the effects of analgesics (Aslaksen et al., 2015;Bingel et al., 2011). On the other hand, the upward information about other people's judgements that was used in another experimental study to alter the memory of the frequency of somatic and psychological symptoms was also shown to be ineffective (Merckelbach et al., 2018). ...
Background:
Previous studies have shown that pain memories have a profound impact on subsequent pain experiences. This study investigated whether pain ratings derived from other people can modify an individual's memory of past pain. This study also examined whether pain memory modified by others' pain ratings determines subsequent pain experiences.
Methods:
Participants were divided into two groups: an experimental group and a control group. Participants in both groups were exposed to pain stimulation; they then recalled its intensity twice over a period of time; after a break, they were again exposed to pain stimulation of the same intensity. The final sample consisted of 53 participants. The only difference between the experimental group and the control group was that in the former the pain ratings of other alleged participants were presented between the two consecutive pain recalls. These ratings suggested that other people experienced the same pain as less intense.
Results:
The pain ratings derived from other people did not alter the pain memory; nevertheless, they affected an individual's next pain experience even for a certain period of time after their presentation. This type of pain-related information shaped participants' subsequent pain experiences regardless of their empathy, conformity, and susceptibility to social influence.
Conclusions:
Information on pain derived from other people not only shapes the response to a novel stimulation but also substantially modifies the subsequent experience of that stimulation.
... The placebo and nocebo effect are phenomena where a favorable and detrimental outcome arises from the belief that one has received a beneficial or harmful treatment (Chavarria et al. 2017). Both placebo and nocebo effects have been shown to modulate the efficacy and tolerability of exercise interventions and clinical treatments (Aslaksen et al. 2015). ...
Rating of perceived exertion (RPE) is used to subjectively quantify the perception of physical activity, breathlessness or dyspnea, and leg discomfort (RPElegs) during exercise. However, it is unknown how dyspnea or RPElegs can be influenced by expectations. Thirty healthy, active participants (19 males, 11 females) completed five, 5-minute submaximal cycling trials at 60% peak work rate. We deceived participants by telling them they were inspiring different hypoxic and hyperoxic gases, when in fact they breathed room air. Cardiorespiratory variables were similar between the trials, however, dyspnea and RPElegs evaluated with a Borg scale changed in a dose–response manner. When participants believed they were breathing 15% O2, they significantly increased dyspnea +0.70 ± 0.2 units (p = 0.03) compared to room air, whereas RPElegs was unchanged +0.35 ± 0.1 units (p = 0.70). When participants believed they were breathing 15% O2, they significantly increased dyspnea +1.05 ± 0.4 units (p = 0.003) compared to 23% hyperoxic condition, whereas RPElegs was unchanged +0.35 ± 0.1 units (p = 0.70). We found that dyspnea during exercise is susceptible to expectancy, without any accompanying physiological changes. Given coaches and clinicians use perceived exertion to prescribe exercise intensity and evaluate treatments, our findings show that the effect of expectations must be considered when interpreting sensations of breathlessness.
... e seventh lecture discussed the importance of maximizing the placebo effect and minimizing the nocebo effect within the PT setting. 90 A PT presented multiple research studies on the clinical uses of both the placebo effect 91,92 and the nocebo effect 93,94 in affecting treatment successes as well as how provider warmth and competence affects treatment success 95 and perceived time spent with the patient. 96 Additionally, several research articles on the effectiveness of placebo surgery for conditions such as meniscus tears, 97,98 shoulder labral tears, 99 subacromial impingement, 100 and tendinopathy 101 were discussed as well as a systematic review on sham surgery. ...
Background and Purpose
Pain education within physical therapist educational programs needs to continually evolve to meet current best practice guidelines. This model presentation describes the successful implementation of a pain curriculum using various active learning approaches including VoiceThread assignments in an entry-level physical therapist educational program.
Method/Model Description and Evaluation
An 8-week curriculum was developed to assist students in meeting the synthesis and evaluation learning objectives of the International Association for the Study of Pain (IASP) curricular guidelines. Active learning homework assignments allowed students to practice communicating difficult pain principles while receiving constructive feedback. Course outcomes were measured through changes in a modified version of the Pain Attitude and Beliefs Scale (PABS), the Pain Care Confidence Scale (PCCS), qualitative student feedback, and performance on both practical and written examinations.
Outcomes
All students passed the practical examination where they successfully demonstrated pain principle communication skills. The students showed less biomedical beliefs in 5 of the 7 PABS biomedical subscale questions and greater biopsychosocial beliefs in 2 of the 7 biopsychosocial subsections ( P < .05). Student scores on the PCCS also improved significantly ( P < .05) from 5.0 to 8.1 on the combined confidence level for treating patients in pain.
Discussion and Conclusion
Implementation of the IASP curriculum within an entry-level physical therapist education program resulting in positive results in student learning and changing beliefs using a combined lecture and active learning approach.
... Placebo response is a powerful determinant of health outcomes in several disorders and may directly interfere with tolerance and efficacy of pharmacological therapy. 1,2 Highevidence studies have demonstrated the importance of placebo and nocebo effects, with symptom relief in conditions such as pain, depression, Parkinson disease, hypertension, arthritis, migraine, cancer, and asthma. 20 This result reaches 75% of the overall treatment in conditions such as fibromyalgia 37 and osteoarthritis. ...
Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. Thus, this meta-analysis aims to analyze how different routes of administration affect the placebo response in chronic migraine (CM). We conducted a meta-analysis with 7 randomized, double-blind, placebo-controlled clinical trials, with 5672 patients older than 18 years who suffer from CM without associated comorbidities. We compared those who received a placebo-administered agent for the preventive treatment of CM subcutaneous, endovenous, or oral against those who received multiple head injections. The primary outcome was reduction in the number of days with migraine in the month assessed at 12, 16, and 24 weeks of treatment compared with baseline. Our study shows that placebo responses were greater when botulinum toxin was applied to the head, followed by intravenous injection of the anti-calcitonin gene-related peptide monoclonal antibody eptinezumab. Oral topiramate and subcutaneous monoclonal showed no difference, being inferior to head injection. Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.
... The nocebo effect is defined as a harmful result of patients' doubts or negative expectations about the treatment (Blasini et al., 2018). Evidence has been found that both the placebo and nocebo effects can substantially affect the efficacy of the drug as well as nondrug treatments (Amanzio et al., 2001;Aslaksen et al., 2015). Therefore, nocebo effects can affect the accurate determination and evaluation of therapeutic drugs. ...
Background: The successful application of randomized, double-blind placebo-controlled studies requires maximum blinding. Organoleptic properties of the placebo should be similar to the drug, making it difficult to distinguish between the two. The uniqueness of traditional Chinese medicine (TCM) preparations makes it challenging to prepare placebo. Evaluation of the TCM placebo simulation effect can determine whether the preparation of placebo can be genuinely blind in clinical trials. There is still a lack of well-established methods to evaluate TCM placebos. Hence, this study aimed to explore the evaluation methodology of TCM placebo simulation.
Methods: An independent evaluation method and three comparative evaluation methods were proposed, and three dosage forms (oral liquid, capsule, and granule) were tested. The independent evaluation, in which each person was given an experimental drug or a placebo, gave an overall assessment of organoleptic properties in a blind state. We comparatively evaluated the similarity in organoleptic properties between the experimental drug and placebo. According to different distribution methods, we divided comparative evaluation methods into three. In method 1, the evaluator was given the experimental drug and placebo and was told that there must be a placebo among them. In method 2, each evaluator was randomly assigned to the combination group or two investigational drugs group. In method 3, the evaluator was assigned to a set of three coded samples, numbered by random three-digit numbers, each different, two of which were identical, and the two samples were equally frequent.
Results: In the independent evaluation, there was no difference between TCM placebo and experimental drugs in a blind state at the level of p = 0.05. Even though the comparative evaluation methods enabled identification of potential differences between the two samples, methods 2 and 3 were better than method 1 in eliminating psychological factors. Also, in method 3, the completely random method combined with the blind method eliminated the subjectivity and objectivity bias and improved the experiment’s credibility compared with the previous two methods.
Conclusion: Regardless of the methods that could evaluate the placebo’s simulated effect in actual clinical trials, we suggest that independent evaluation and comparative evaluation (method 3) should be combined to reflect better whether the placebo is truly blind.
... Ayrıca, ağrı açısından yüksek düzeyde korku ve kaygı düzeyine sahip hastaların belirlenmesi, hekimin tedavinin etkilerini optimize etmek için hasta uyumunu artırıcı yöntemlere yönelmesine yardımcı olabilir. 32 Benzer şekilde, farmakolojik olarak aktif ilaçların etkililiği, çelişkili bilgiler verildiğinde büyük ölçüde farklılık gösterebilmektedir. Örneğin; Lupa-rello ve ark.nın astım hastaları üzerinde yaptıkları çalışmada, hastalara irritan özelliklere sahip bir alerjen olarak tanıttıkları serum fizyolojiği inhaler yoldan verdiklerinde hastaların yaklaşık yarısında havayolu direncinde artış saptanmıştır. ...
The placebo effect ('I will please' in English) is a common concept in both clinical trials and clinical practice in medicine. On the other hand, the nocebo effect ('I will get harm' in English), which has significant implications for clinical outcomes and is defined as the 'dark side' of placebo, is another important concept. In clinical practice, negative expectations arising from patient-physician communication and patient psychology can lead to detrimental results. The nocebo effect can be seen as a reduced recovery or an increased frequency of side effects, regardless of the dose and pharmacological properties of the drug. In order to identify nocebo effects, the side effects seen in the study should be systematically evaluated and compared with the side effects in the group receiving the drug whose efficacy is investigated. These effects may cause insecurity, decreased clinical response, and in some cases, discontinuation from the trials. Clinical findings beyond the potential side effects also demonstrate the importance of this effect. Studies on the nocebo effect are ongoing and many neurobiological processes have been implicated. To better interpret the results of randomized controlled clinical trials, the nocebo effects should be well known. In this review, besides the aim of raising awareness about nocebo effects, also possible mechanisms, how to define nocebo effects in scientific studies and clinical practice, and recommendations to reduce these effects were aimed.
... Interestingly, placebo and nocebo effects often come along with emotional responses, such as anticipatory anxiety (nocebo) or positive feelings of relief and reward (placebo), which-to some degree-might mediate the modulation of (pain) symptoms (22)(23)(24). For instance, Aslaksen and colleagues showed that a nocebo instruction suggesting hyperalgesic effects caused by an applied cream led to a pain increase, which was meditated by subjective and physiological indices of stress (25). However, when applying a mere conditioning procedure without explicit placebo or nocebo instructions, the role of negative affect might be less relevant (26). ...
According to the motivational priming hypothesis, unpleasant stimuli activate the motivational defense system, which in turn promotes congruent affective states such as negative emotions and pain. The question arises to what degree this bottom–up impact of emotions on pain is susceptible to a manipulation of top–down-driven expectations. To this end, we investigated whether verbal instructions implying pain potentiation vs. reduction (placebo or nocebo expectations)—later on confirmed by corresponding experiences (placebo or nocebo conditioning)—might alter behavioral and neurophysiological correlates of pain modulation by unpleasant pictures. We compared two groups, which underwent three experimental phases: first, participants were either instructed that watching unpleasant affective pictures would increase pain (nocebo group) or that watching unpleasant pictures would decrease pain (placebo group) relative to neutral pictures. During the following placebo/nocebo-conditioning phase, pictures were presented together with electrical pain stimuli of different intensities, reinforcing the instructions. In the subsequent test phase, all pictures were presented again combined with identical pain stimuli. Electroencephalogram was recorded in order to analyze neurophysiological responses of pain (somatosensory evoked potential) and picture processing [visually evoked late positive potential (LPP)], in addition to pain ratings. In the test phase, ratings of pain stimuli administered while watching unpleasant relative to neutral pictures were significantly higher in the nocebo group, thus confirming the motivational priming effect for pain perception. In the placebo group, this effect was reversed such that unpleasant compared with neutral pictures led to significantly lower pain ratings. Similarly, somatosensory evoked potentials were decreased during unpleasant compared with neutral pictures, in the placebo group only. LPPs of the placebo group failed to discriminate between unpleasant and neutral pictures, while the LPPs of the nocebo group showed a clear differentiation. We conclude that the placebo manipulation already affected the processing of the emotional stimuli and, in consequence, the processing of the pain stimuli. In summary, the study revealed that the modulation of pain by emotions, albeit a reliable and well-established finding, is further tuned by reinforced expectations—known to induce placebo/nocebo effects—which should be addressed in future research and considered in clinical applications.
... Subjective pain scores increased by 20% (mean difference 0.30 cm) in the nocebo versus control conditions. This effect size is comparable to other experimental studies of nocebo effects (Aslaksen, Zwarg, Eilertsen, Gorecka, & Bjørkedal, 2015, Babel et al., 2017. The main aim of the present study was, however, to determine whether sleep restriction potentiated nocebo-induced changes in pain, but this was not supported. ...
Background:
The increased pain sensitivity following reduced sleep may be related to changes in cortical processing of nociceptive stimuli. Expectations shape pain perception and can inhibit (placebo) or enhance (nocebo) pain. Sleep restriction appears to enhance placebo responses; however, whether sleep restriction also affects nocebo responses remains unknown. The aim of the present study was to determine whether sleep restriction facilitates nocebo-induced changes in pain and pain-evoked cortical potentials.
Methods:
In an experimental study with a crossover design, the sensitivity to electrically induced pain was determined in 53 nurses under two sleep conditions, after habitual sleep and after two consecutive nights at work. Nocebo was induced by conditioning one-third of the pain stimuli. Pain-elicited cortical event-related potentials were recorded by electroencephalography (EEG). Data were analysed both in the time-domain (N2P2 amplitude) and in the time-frequency domain (ERP magnitude). Sleepiness and vigilance were also assessed.
Results:
Both nocebo alone and sleep restriction alone increased the sensitivity to electrically induced pain. However, no interaction effect was found. Moreover, the magnitude of the pain-elicited responses increased after sleep restriction and decreased after nocebo expectation, suggesting that nocebo is probably not an underlying mechanism for the commonly observed hyperalgesia induced by sleep restriction.
Conclusions:
The present work addresses whether sleep restriction, known to increase the sensitivity of the pain system, facilitates nocebo-induced hyperalgesia. Our findings suggest that this is not the case, indicating that the increased sensitivity of the pain system following nocebo and sleep restriction are mediated by different cortical mechanisms. This article is protected by copyright. All rights reserved.
... Our findings are in accordance with several previous studies on different indications and treatments which suggested that anticipation of negative treatment consequences can lead to AEs [7,8,[36][37][38][39][40]. However, most previous studies were rather artificial regarding the intervention and setting (e.g., negative versus positive suggestions during an investigator-induced pain stimuli in a laboratory) and thus their applicability to treatment with an active intervention under routine care is questionable. ...
Background:
The term "nocebo effect" describes the phenomenon that the mere knowledge and anticipation of possible negative consequences of an intervention can increase the probability of experiencing these consequences. Our objective was to assess whether different information presentations on adverse events (AEs) in package information leaflets (PILs) could influence the nocebo effect.
Methods:
We included patients undergoing orthopaedic surgery in this pilot randomised controlled trial (pRCT). Patients were assigned by random, computerised and centralised allocation to one of three groups: Simplified-PIL, No-PIL or Standard-PIL on ibuprofen. The Simplified-PIL was written in plain language, and AEs were reported with a focus on avoiding biased risk perception. Only the outcome assessment was blinded.
Results:
We included 35, 33 and 34 patients in the Simplified-PIL, No-PIL and Standard-PIL groups, respectively. All patients were included in the intention-to-treat analysis. Six patients in the Simplified-PIL, four in the No-PIL and eight in the Standard-PIL group reported an AE. This corresponds to relative risks of 0.80 (95% confidence interval (CI) 0.27-1.90) for the Simplified-PIL and 0.50 (95% CI 0.14-1.46) for the No-PIL compared with the Standard-PIL group. The Simplified-PIL increased knowledge, reduced anxiety and improved adherence, although statistical uncertainty was high for all of these outcomes.
Conclusions:
This pRCT provides the first hints on the way information on AEs is reported in PILs can affect the nocebo effect. This pRCT shows that a definitive RCT is feasible. If the results are confirmed in a definitive large RCT, a revision of the current practice for designing PILs should be considered.
Trial registration:
ClinicalTrials.gov identifier: NCT03428035. Registered 2 February 2018.
... Nocebo effects can cause reduced efficacy of treatments (1,2) and side effects which are not attributable to the pharmacological or other active ingredients of the treatment (3). Broadly defined, nocebo effects are negative effects caused by psychological and contextual factors of the treatment. ...
Relevance: Informing patients about potential adverse events as part of the informed consent may facilitate the development of nocebo-driven drug adverse events (nocebo side effects).
Objective: To investigate whether informing about the nocebo effect using a short information sheet can reduce nocebo side effects.
Methods: A total of N = 44 participants with weekly headaches for at least 6 months were recruited using the cover story of a clinical trial for a headache medicine. In reality, all participants took a placebo pill and were randomized to the nocebo information group or the standard leaflet group. Participants were instructed to read the bogus medication leaflet entailing side effects information shortly before pill intake. The nocebo group additionally received an explanation about the nocebo effect as part of the leaflet. Questionnaires were completed at baseline, 2 min, and 4 days after the pill intake. We conducted general linear models with bootstrap sampling. Baseline symptoms were included as a covariate.
Results: Most participants (70.5%) reported nocebo side effects at 2 min. Participants who received the nocebo information (n = 24) reported less nocebo symptoms than the control group (n = 20) (estimated difference: 3.3, BCa 95% CI [1.14; 5.15], p = 0.01, Cohen’s d = 0.59). Baseline symptoms, perceived sensitivity to medicine, and side effect expectations each moderated the group effect (estimated difference in slope: 0.47, BCa 95% CI [0.19; 0.73], p = 0.001, d = 0.75; 1.07 [0.27; 1.61], p = 0.006, d = 0.73; 1.57 [0.38; 2.76], p = 0.02, d = 0.58). No group differences were found at 4-day follow-up. After revealing the actual aim of the study, 86% of the participants evaluated the nocebo information to be helpful in general.
Conclusions: Results provide the first evidence that informing about the nocebo effect can reduce nocebo side effects.
... 24,49,69,79 Laboratory research has demonstrated robust nocebo hyperalgesia effects from verbal treatment information such as experimenter warnings and by nonverbal indicators of adverse treatment effects, such as social observations. 3,6,20,80 In practice, a verbal warning about potential pain due to a medical condition (eg, broken leg), course of a disease (eg, rheumatoid arthritis), or treatment procedure (eg, surgery) may lead to nocebo hyperalgesia. 19,81 Nocebo hyperalgesia poses a challenge for clinical care. ...
There is an ethical obligation to notify individuals about potential pain associated with diagnoses, treatments, and procedures; however, supplying this information risks inducing nocebo hyperalgesia. Currently there are few empirically-derived strategies for reducing nocebo hyperalgesia. Since nocebo effects are linked to negative affectivity, we tested the hypothesis that a positive affect induction can disrupt nocebo hyperalgesia from verbal suggestion. Healthy volunteers (N =147) were randomly assigned to conditions in a 2 (Affect Induction: Positive vs. Neutral) by 2 (Verbal Suggestion: No Suggestion vs. Suggestion of Pain Increase) between-subjects design. Participants were induced to experience positive or neutral affect by watching movie clips for 15 mins. Next, participants had an inert cream applied to their non-dominant hand and suggestion was manipulated by telling only half the participants the cream could increase the pain of the upcoming cold pressor test. Subsequently, all participants underwent the cold pressor test (8C ±.04C), wherein they submerged the non-dominant hand and rated pain intensity on numerical rating scales every 20 sec up to two mins. In the neutral affect conditions, there was evidence for the nocebo hyperalgesia effect: participants given the suggestion of pain displayed greater pain than participants not receiving this suggestion, ps<.05. Demonstrating a blockage effect, nocebo hyperalgesia did not occur in the positive affect conditions, ps>.5. This is the first study to show that positive affect may disrupt nocebo hyperalgesia thereby pointing to a novel strategy for decreasing nocebo effects without compromising the communication of medical information to patients in clinical settings.
... 90,91 Furthermore, the efficacy of active topical or opioid analgesia can be either enhanced or abolished by verbal suggestions that induce positive or negative expectations and emotions, respectively. 92,93 Thus, by measuring patients' perception of the intervention and their expectations towards treatment outcome early in the trial, it may be possible to test how that influences the outcome in the placebo and active arm thereby offering an alternative way of measuring the placebo component of the treatment. Such an approach may also give a better indication of whether blinding has been maintained. ...
Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in pharmacological trials and marked placebo effects are found in neurostimulation and surgical trials, thereby posing the question whether non-pharmacological interventions should be placebo-controlled to a greater extent. In this narrative review we discuss how the knowledge of placebo mechanisms may help to improve placebo control in pharmacological and non-pharmacological trials. We review the psychological, neurobiological, and genetic mechanisms underlying placebo analgesia and outline the current problems and potential solutions to the challenges with placebo control in trials on pharmacological, neurostimulation, and surgical interventions. We particularly focus on how patients' perception of the therapeutic intervention, and their expectations towards treatment efficacy may help develop more precise placebo controls and blinding procedures and account for the contribution of placebo factors to the efficacy of active treatments. Finally, we discuss how systematic investigations into placebo mechanisms across various pain conditions and types of treatment are needed in order to ‘personalise’ the placebo control to the specific pathophysiology and interventions, which may ultimately lead to identification of more effective treatment for pain patients. In conclusion this review shows that it is important to understand how patients' perception and expectations influence the efficacy of active and placebo treatments in order to improve the test of new treatments. Importantly, this applies not only to assessment of drug efficacy but also to non-pharmacological trials on surgeries and stimulation procedures.
... In the long history of placebo/nocebo research, the fundamental demonstrations of placebo/nocebo effects have been largely confined to the pain or motor domains [6][7][8][9] . But are cognitive functions similarly amenable to placebo and nocebo effects? ...
Inactive interventions can have significant effects on cognitive performance. Understanding the generation of these cognitive placebo/nocebo effects is crucial for evaluating the cognitive impacts of interventional methods, such as non-invasive brain stimulation (NIBS). We report both cognitive placebo and nocebo effects on reward-based learning performance induced using an active sham NIBS protocol, verbal suggestions and conditioning in 80 healthy participants. Whereas our placebo manipulation increased both expected and perceived cognitive performance, nocebo had a detrimental effect on both. Model-based analysis suggests manipulation-specific strategic adjustments in learning-rates: Participants in the placebo group showed stronger learning from losses and reduced behavioral noise, participants in the nocebo group showed stronger learning from gains and increased behavioral noise. We conclude that experimentally induced expectancy can impact cognitive functions of healthy adult participants. This has important implications for the use of double-blind study designs that can effectively maintain blinding in NIBS studies.
... Si ces aggravations sont souvent attribuées à des effets nocebo [6][7], cette dénomination n'est pas toujours appropriée. En effet, les effets nocebo lato-sensu correspondent à l'aggravation réelle de la douleur, du fait de la libération de différents neuromédiateurs comme la cholécystokinine (laquelle antagonise aussi les effets placebos) [8][9], de la même manière que les effets nocebo stricto sensu correspondent à l'induction d'effets indésirables réellement perçus dans les suites d'une suggestion négative. ...
Résumé
En médecine, l’effet Hawthorne positif correspond à la moindre expression d’un symptôme en présence d’un évaluateur. Il s’additionne au moindre ressenti que procure l’effet placebo. Quand le symptôme est au contraire surexprimé, consciemment ou inconsciemment, il s’agit d’un effet Hawthorne négatif, à distinguer des effets nocebo, durant lesquels le symptôme est réellement plus ressenti. Un exemple d’effet Hawthorne négatif est celui des patients évaluant calmement leurs douleurs à onze sur dix. Les motifs d’effets Hawthorne négatifs sont nombreux : souhait d’être davantage considéré(e), ou pris(e) en charge prioritairement ; crainte de ne pas valider les critères d’obtention d’un nouveau traitement ou d’intégration dans un essai thérapeutique ; conformisme culturel ou de circonstance, comme de ne pas annuler une intervention chirurgicale lorsqu’une amélioration survient in extremis ; disease mongering ou stratégie de Knock ; désir d’être pris au sérieux par son entourage ; recherche de bénéfices secondaires ; utilisation de l’évaluation pour exprimer sa frustration d’être malade, ou son dépit de ne plus être choyé ; décalage entre les attentes d’un soulagement complet et l’efficience réelle des traitements ; majoration des douleurs, à l’origine de la démonétisation de leur chiffrage, par anxiété, culpabilité, dépression, nervosisme, catastrophisme, kinésiophobie, ou du fait d’évaluations répétées avec des procédés comportant des suggestions négatives, comme l’évocation de la pire douleur imaginable. La succession de forts effets Hawthorne négatifs avant prescription, puis de forts effets Hawthorne positifs après introduction des thérapeutiques, pourrait, plus que l’effet placebo, expliquer une bonne part des améliorations observées dans le traitement des douleurs.
Research suggests that negative affective states, such as fear and anxiety that accompany placebo treatment may be considered predictors of placebo hypoalgesia and nocebo hyperalgesia. There is also data showing that the likelihood of developing nocebo hyperalgesia is related to the relatively stable tendency to experience these negative emotions. We aimed to summarize the current state-of-the-art in studies and theoretical models on the role of fear and anxiety in placebo hypoalgesia/nocebo hyperalgesia, with a clear differentiation between these emotions. The role of fear and anxiety accompanying placebo treatment in shaping placebo effects is often studied, but less attention has been given to pretreatment emotional states. We propose a model that combines knowledge from the emotional and pain paradigms with the current research on placebo hypoalgesia and nocebo hyperalgesia to present the involvement of fear and anxiety as traits, as well as pretreatment and posttreatment states of fear and anxiety to placebo effects. The main assumption of the model is that trait fear, trait anxiety, and related pretreatment affective states impact pain perception differently. Heightened fear is associated with decreased pain perception, while heightened anxiety is linked to increased pain perception. Consequently, heightened pretreatment fear may lead to reduced nocebo hyperalgesia and enhanced placebo hypoalgesia, while heightened pretreatment anxiety may result in decreased placebo hypoalgesia and increased nocebo hyperalgesia. In conclusion, we propose future research directions and clinical applications of the model.
Nocebo hyperalgesia is a pervasive problem in which the treatment context triggers negative expectations that exacerbate pain. Thus, developing ethical strategies to mitigate nocebo hyperalgesia is crucial. Emerging research suggests that choice has the capacity to reduce nocebo side effects, but choice effects on nocebo hyperalgesia have not been explored. This study investigated the impact of choice on conditioned nocebo hyperalgesia using a well-established electrocutaneous pain paradigm where increases in noxious stimulation were surreptitiously paired with the activation of a sham device. In study 1, healthy volunteers (N = 104) were randomised to choice over (nocebo) treatment administration, nocebo administration without choice, or a natural history control group. Nocebo hyperalgesia was greater for those with choice than no choice, suggesting that choice increased rather than diminished nocebo hyperalgesia. Study 2 tested whether providing positive information about the benefits of choice in coping with pain could counteract heightened nocebo hyperalgesia caused by choice. A different sample of healthy adults (N = 137) were randomised to receive nocebo treatment with choice and positive choice information, choice only, or no choice. The positive choice information failed to attenuate the effect of choice on nocebo hyperalgesia. The current results suggest that, rather than decreasing nocebo hyperalgesia, treatment choice may exacerbate pain outcomes when a painful procedure is repeatedly administered. As such, using choice as a strategy to mitigate nocebo outcomes should be treated with caution.
Objetivo: El efecto nocebo representa una preocupación creciente en el ámbito clínico. Los efectos Nocebo ocurren cuando el contexto del tratamiento genera expectativas negativas que desencadenan la experiencia o el empeoramiento de síntomas negativos más allá de cualquier efecto atribuible al tratamiento en sí. A pesar de identificarse en una variedad de resultados y condiciones, desde el dolor hasta la enfermedad de Parkinson, no ha habido un intento de cuantificar sistemáticamente los efectos nocebo en todos los resultados de salud. Por lo tanto, el propósito de la presente revisión fue revisar y meta analizar sistemáticamente la literatura sobre nocebo para cuantificar el tamaño del efecto nocebo en todos los resultados y examinar qué factores moderan el tamaño del efecto nocebo, incluido el proceso de inducción, el tipo de tratamiento o la salud. resultado. Método: Las búsquedas sistemáticas en PubMed, PychInfo, Medline y Web of Science identificaron 130 (n = 8,219) estudios elegibles independientes. Para ser incluidos, los estudios debían incluir tanto un grupo/condición de nocebo como un grupo de control, que se compararon para aislar el tamaño del efecto de nocebo. Resultados: En general, la magnitud del efecto nocebo fue media (g = 0.522) y muy heterogénea. Surgieron dos moderadores clave: los resultados de salud y el proceso de inducción. En este caso, el efecto nocebo fue medio para la mayoría de los resultados somáticos y afectivos, sin ningún efecto significativo sobre el empeoramiento del rendimiento cognitivo. Además, la inducción de efectos nocebo a través de la instrucción en combinación con el condicionamiento produjo mayores efectos nocebos. Conclusiones: La presente revisión sugiere que los efectos nocebo pueden inducirse de manera confiable en todos los resultados de salud somáticos, y que las intervenciones dirigidas al efecto de las instrucciones serán de importancia crítica para reducir la aparición de efectos nocebo.
Placebo effects, positive treatment outcomes that go beyond treatment processes, can alter sensations through learning mechanisms. Understanding how methodological factors contribute to the magnitude of placebo effects will help define the mechanisms by which these effects occur. We conducted a systematic review and meta-analysis of experimental placebo studies in cutaneous pain and itch in healthy samples, focused on how differences in methodology contribute to the resulting placebo effect magnitude. We conducted meta-analyses by learning mechanism and sensation, namely, for classical conditioning with verbal suggestion, verbal suggestion alone, and observational learning, separately for pain and itch. We conducted subgroup analyses and meta-regression on the type of sensory stimuli, placebo treatment, number of acquisition and evocation trials, differences in calibrated intensities for placebo and control stimuli during acquisition, age, and sex. We replicated findings showing that a combination of classical conditioning with verbal suggestion induced larger placebo effects on pain (k = 68, g = 0.59) than verbal suggestion alone (k = 39, g = 0.38) and found a smaller effect for itch with verbal suggestion alone (k = 7, g = 0.14). Using sham electrodes as placebo treatments corresponded with larger placebo effects on pain than when topical gels were used. Other methodological and demographic factors did not significantly affect placebo magnitudes. Placebo effects on pain and itch reliably occur in experimental settings with varied methods, and conditioning with verbal suggestion produced the strongest effects. Although methods may shape the placebo effect to some extent, these effects appear robust overall, and their underlying learning mechanisms may be harnessed for applications outside the laboratory.
Despite the theoretical prominence of expectancy and anxiety as potential mechanisms of the nocebo effect, not all studies measure expectancy and/or anxiety, and there are inconsistent findings among those that do. The purpose of the present study was to systematically review and meta-analyse available data to evaluate the relationship between expectancy and anxiety and the nocebo effect. The two key questions were: (1) whether nocebo manipulations influence expectancy and anxiety; and (2) whether expectancy and anxiety are associated with the subsequent nocebo effect. Fifty-nine independent studies (n = 3129) were identified via database searches from inception to 1st August 2021. Nocebo manipulations reliably increased negative expectancy with a large effect (g = .837) and state anxiety with a small effect (g = .312). Changes in expectancy and state anxiety as a result of the nocebo manipulation were associated with larger nocebo effects (r = .376 and .234, respectively). However, there was no significant association between dispositional anxiety and the nocebo effect (baseline state anxiety, r = .061; trait anxiety, r = .021; illness-specific anxiety, r = .016). These findings support theories that rely on situationally-induced expectancy and anxiety, but not dispositional anxiety, to explain nocebo effects. Importantly, being malleable, these findings suggest that interventions that target maladaptive negative expectancies and state anxiety could be beneficial for reducing the harm nocebo effects cause across health settings. Recommendations for future research are discussed.
Attribute framing presents an ethically sound approach for reducing adverse nocebo effects. In past studies, however, attribute framing has not always decreased nocebo effects. The present study used a sham tDCS procedure to induce nocebo headaches to explore factors that may contribute to the efficacy of attribute framing. Participants (N = 174) were randomized to one of three between-subject conditions: a no-headache instruction (control) condition and two conditions in which headaches were described as either 70% likely (negative framing) to occur or 30% unlikely (positive framing) to occur. Results revealed nocebo headaches in both framing conditions, as compared to the control condition. Attribute framing did not influence headache measures recorded during the sham tDCS task, but positive framing did have a modest influence on one of two headache items completed after the task. Results suggest that attribute framing could have a stronger influence on delayed nocebo effect measures or retrospective symptom reports; a finding that may explain inconsistencies in the existing framing nocebo effect literature. Exploratory analyses also revealed that low negative affect was associated with stronger nocebo and attribute framing effects, although these effects were found on only a few headache measures. It is concluded that researchers should further investigate the influence of attribute framing on nocebo headaches as a function of both timing and emotional factors.
Full text version can be found here: https://rdcu.be/cGZRq
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.
Introduction
Randomized clinical trials (RCTs) are useful to study the role of individual and contextual factors in which therapies vs placebos are administered, and to provide an important perspective for understanding the phenomenon of nocebo-related risks.
Areas covered
The results of nocebo effects in RCTs placebo groups, measured in terms of adverse events (AEs) and dropouts, will be presented as an explicative framework for the COVID-19 pandemic. Currently, SARS-CoV-2 vaccines are the only RCTs routinely conducted during the pandemic. Information about efficacy and safety of different vaccines, represent a fertile ground for nocebo phenomena. Individual and contextual factors will be emphasized in order to understand the presence of a refusal of immunization associated with a specific vaccine considered less effective and safe. Critical aspects and some guidelines will be presented in order to counteract nocebo effects and to improve adherence to drug treatments and the vaccination campaign.
Expert opinion
The nocebo effect could explain the presence of a strong resistance in European countries to immunization with a vaccine perceived as less effective, compared to others. Increased awareness of the nocebo effect would be relevant as it could lead to a greater participation in the vaccination campaign and in protecting individuals against SARS-CoV-2 infection.
Keywords
: Randomized clinical trials, adverse events, nocebo effects, COVID-19
Lack of standardization and unblinding threaten the research of mechanisms involved in expectancy effects on pain. We evaluated a computer-controlled virtual experimenter (VEx) to avoid these issues. Fifty-four subjects underwent a baseline-retest heat pain protocol. Between sessions, they received an expectancy manipulation (placebo or no-treatment) delivered by VEx or text-only control condition. The VEx provided standardized “social” interaction with the subjects. Pain ratings and psychological state/trait measures were recorded. We found an interaction of expectancy and delivery on pain improvement following the intervention. In the text conditions, placebo was followed by lower pain, whereas in the VEx conditions, placebo and no-treatment were followed by a comparable pain decrease. Secondary analyses indicated that this interaction was mirrored by decreases of negative mood and anxiety. Furthermore, changes in continuous pain were moderated by expectation of pain relief. However, retrospective pain ratings show an effect of expectancy but not of delivery. We conclude that we successfully applied an automated protocol for inducing expectancy effects on pain. The effect of the VEx regardless of treatment may be due to interactions of attention allocation and locus of control. This points to the diversity of expectancy mechanisms, and has implications for research and computer-based treatment applications.
Once considered nuisance variance in clinical trials, placebo
effects and nocebo effects are now widely recognized as
important and mutable psychobiological contributors to
mental and physical health. Psychological theory explaining
these effects emphasizes associative learning and
conscious expectations. It has long been suggested, however,
that affective states such as moods, emotions, and
distress could play a significant role. In this paper, we draw
together and review the empirical data linking affective
states to placebo and nocebo effects. To organize this
disparate literature, three questions are addressed:
(1) Does pre‐existing state and trait affect modulate placebo
and nocebo effects? (2) Does administering placebo
and nocebo treatments change affective states, and if so,
does the resulting affect causally influence placebo and
nocebo effects? Finally, (3) Can placebo treatments be
successfully employed as a regulation strategy to modulate
different affective states? In reviewing the evidence in
relation to these three questions, it is clear that affect does
play a key role in placebo and nocebo effects in many circumstances,
and further, there may be a reciprocal dynamic
at play between a treatment event, affect, and placebo/
nocebo effects. The paper concludes by discussing implications
for theory and intervention and recommends future
research priorities.
Once considered nuisance variance in clinical trials, placebo effects and nocebo effects are now widely recognized as important and mutable psychobiological contributors to mental and physical health. Psychological theory explaining these effects emphasizes associative learning and conscious expectations. It has long been suggested, however , that affective states such as moods, emotions, and distress could play a significant role. In this paper, we draw together and review the empirical data linking affective states to placebo and nocebo effects. To organize this disparate literature, three questions are addressed: (1) Does pre-existing state and trait affect modulate placebo and nocebo effects? (2) Does administering placebo and nocebo treatments change affective states, and if so, does the resulting affect causally influence placebo and nocebo effects? Finally, (3) Can placebo treatments be successfully employed as a regulation strategy to modulate different affective states? In reviewing the evidence in relation to these three questions, it is clear that affect does play a key role in placebo and nocebo effects in many circumstances , and further, there may be a reciprocal dynamic at play between a treatment event, affect, and placebo/ nocebo effects. The paper concludes by discussing implications for theory and intervention and recommends future research priorities. Soc Personal Psychol Compass. 2020;e12575. wileyonlinelibrary.com/journal/spc3
Background: Placebo/nocebo effects involve the autonomic nervous system, including cardiac activity, but studies have reported inconsistent findings on how cardiac activity is modulated following a placebo/nocebo effect. However, no systematic review has been conducted to provide a clear picture of cardiac placebo responses.
Objective: The main goal of the present study is to review the effects of placebo analgesia and nocebo hyperalgesia on cardiac activity as measured by blood pressure, heart rate, and heart rate variability.
Methods: Using several Boolean keyword combinations, the PubMed, EMBASE, PsycINFO, Cochrane Review Library, and ISI Web of Knowledge databases were searched until January 5, 2020, to find studies that analyzed blood pressure, heart rate, or heart rate variability indexes following a placebo analgesic/nocebo hyperalgesic effect.
Results: Nineteen studies were found, with some reporting more than one index of cardiac activity; eight studies were on blood pressure, 14 studies on heart rate, and six on heart rate variability. No reliable association between placebo/nocebo effects and blood pressure or heart rate was found. However, placebo effects reduced, and nocebo effects increased low-frequency heart rate variability, and heart rate variability significantly predicted placebo effects in two studies.
Conclusion: Placebo/nocebo effects can have reliable effects on heart rate variability, but not on heart rate and blood pressure.
Background and aims
The randomized controlled trial (RCT) is currently facing several challenges, one of these being that the placebo response appears to be increasing in RCTs, thereby making it difficult to demonstrate an effect of potentially new treatments over placebo. This problem has primarily been approached by predicting the magnitude of the placebo response via stable factors, such as demographic variables, and/or by developing complex designs aimed at reducing the placebo response in the hope that it will improve the test of the active treatment. Yet, the success of this approach has so far been limited.
Methods
A new approach toward improving the RCT is put forward based on placebo and nocebo mechanism studies, i.e. studies that investigate the mechanisms underlying placebo analgesia and nocebo hyperalgesia. In a series of meta-analyses the magnitude of placebo and nocebo effects were determined. Experimental studies across nociplastic and neuropathic pain conditions and across pharmacological and acupuncture treatments investigated psychological and neurobiological mechanisms underlying these effects. The obtained results were used to make approximations of expectations to see if that could predict the placebo response in RCTs and function as a new way of tapping into the placebo component of treatment effects.
Results
The magnitude of placebo and nocebo effects is large and highly variable. Placebo effects exist across chronic pain conditions with varying degrees of known etiology as well as across pharmacological and non-pharmacological treatments. Patients’ perception of the treatment, the verbal suggestions given for pain relief, and the patients’ expectations toward pain relief contribute to the magnitude of the placebo effect and to pain relief following placebo interventions. Also, unintentional unblinding and patients’ perception of a treatment markedly influence the treatment outcome. By making approximations of expectations toward treatment effects it was possible to predict the magnitude of the placebo response in RCTs.
Conclusions and implications
The new approach of tapping into or directly asking patients about their perception and expectations toward a treatment, along with the account of the natural history of pain, has the potential to improve the information that can be obtained from RCTs. Thus, by interfacing insights from placebo and nocebo mechanism studies, it may be possible to enhance the information that can be obtained from RCTs and to account for a large part of the variability in the placebo component of the overall treatment effect. This approach has the potential to improve the scientific evaluation of treatments, as well as to illustrate how the effect of treatments can be optimized in clinical practice, which is the crux of evidence-based medicine.
Objective
To investigate if frequent stools (“diarrhoea”), infrequent stools (“constipation”), capacity in daily activities and Quality of Life (QoL) differed between patients treated with verum or sham acupuncture, and if patients with more positive treatment expectations differed regarding frequent stools and infrequent stools from patients with less positive treatment expectations.
Methods
In this randomized sham controlled trial, 200 patients received verum traditional penetrating acupuncture or sham acupuncture using a telescopic non-penetrating sham-needle 2–3 times a week during abdominal-pelvic radiotherapy (12 needling sessions during median 5 radiotherapy weeks). The patients registered stool frequency once a week, and registered capacity in daily activities and QoL at the start and end of radiotherapy, and at a one-month follow-up.
Results
In the verum acupuncture group, 29 of 96 answering patients (30 %) experienced frequent stools and 7 (7 %) experienced infrequent stools at least one week of radiotherapy. In the sham acupuncture group, 21 of 97 (22 %) experienced frequent stools (p = 0.175) and 10 (10 %) experienced infrequent stools (p = 0.613). Patients with low treatment expectancy were more likely than other patients to experience frequent stools (60 % versus 26 %, p = 0.014) but not to experience infrequent stools (25 % versus 12 %, p = 0.334).
Conclusion
Penetrating acupuncture was not effective for frequent stools or for infrequent stools and did not improve capacity in daily activities or QoL in patients undergoing pelvic-abdominal irradiation for cancer more than non-penetrating acupuncture. Since patients with low acupuncture treatment expectations were more likely to experience frequent stools compared to other patients, non-specific treatment effects warrant further studies.
Let us leave the conceptual problems aside for a while and keep the phrase placebo effect. Even then there is a multitude of issues to be examined: Do placebo effects exist after all? If they do exist, what is their nature in relation to the human mind and body? How and why have they evolved? Are there placebo effects outside medicine? Is there a certain kind of personality that is prone to placebo effects? Can placebo effects be seen in children and non-human animals? I will begin with the question concerning the existence of placebo effects.
Nocebo effects refer to new or worsening symptoms that develop in response to negative health-related information, beliefs, and/or experiences. In recent years, research on concussion pathophysiology has significantly advanced. Through health campaigns and media coverage, emerging knowledge on the risks of this injury has been quickly disseminated to the public, and nowadays the public perceives concussions as more hazardous to health than ever before. While advancements in concussion-related research and care are of great importance and value, we ask in this article whether the increasing negative publicity regarding concussion also carries any latent costs. Are additional nocebo effects being fostered? To do so, we will review the literature on the psychological and neurobiological processes underlying nocebo effects, present a series of clinical studies demonstrating the ways in which nocebos may impact concussion outcomes both clinically and societally, then speculate on further potential mechanisms for nocebo effects in concussion. We conclude with an outline of the specific efforts one may take to minimize nocebo effects in concussion-related care.
Para mí esta conferencia es un reto profesional; desde que originalmente se programó para septiembre del 2017 acepte el desafío de la invitación; debido al terremoto del 19 de septiembre se tuvo que reprogramar; el terremoto nos obligó a todos a reacomodar muchas cosas y este fue uno de los reacomodos. Intento integrar el trabajo del Dr. Mario Carranza Aguilar (UAM-I y UAS) con lo que hemos venido haciendo en nuestro grupo de investigación clínica: "Mente-Cuerpo" de la Facultad de Psicología de la UNAM. Se incluyen varios niveles de trabajo: comunitario-social (del Dr. Carranza) y el trabajo clínico que hacemos nosotros; nos hemos concentrado en el trabajo con pacientes con dolor crónico (DC). En ambos niveles están incluidos problemas de salud que por su nivel de complejidad incluso han rebasado la capacidad de los especialistas médicos, ellos saben muy bien; por ejemplo, que las personas que sufren de Diabetes Mellitus tipo II no solamente tienen un problema endocrino, también un problema emocional-social; si no se encuadra adecuadamente las intervenciones resultan muy costosas y con pobres resultados. Me declaro un admirador respetuoso de la innovación, soy un "fan" de las personas que son capaces de "abrir brecha", de crear caminos donde no existían. Hace 40 años trabaje en varias cárceles de México y me impresionaba como los presos casi de la nada fabricaban bebidas embriagantes (que necesitaban para sobrevivir en la cárcel), fabricaban una bebida que ellos llamaban: "saltapatras", un fermento que preparaban con cascaras de mandarina y un poco de royal (polvo para hacer los pasteles) y lo dejaban unos dos meses que se destilara en una lata que ocultaban adentro del drenaje con una alambre, así obtenían una bebida que era el "saltapatras" se la tomaban y se iban literalmente
The term nocebo effect refers to the harmful outcomes that result from people’s negative beliefs, anticipations, or experiences related to the treatment rather than the pharmacological properties of the treatment. These outcomes may include a worsening of symptoms, a lack of expected improvement, or adverse events, and they may occur after the active treatment and the placebo that is supposed to imitate it. The nocebo effect is always unwanted and may distort estimates of treatment effectiveness and safety; moreover, it may cause discontinuation of therapy or withdrawal from a trial.
The nocebo effect may be unintentionally evoked by the explanations given by healthcare professionals during a clinical consultation or consent procedures, or by information from other patients, the media, or the Internet. Moreover, it may be a consequence of previous bad experiences with the treatment, through learning and conditioning, and the conditioning may happen without patients’ conscious awareness. In trial settings, a study design, for example lack of blinding, may introduce bias from the nocebo effect.
Unlike the placebo effect, which is usually taken into consideration while interpreting treatment outcomes and controlled for in clinical trials, the nocebo effect is under-recognised by clinical researchers and clinicians. This is worrying, because the nocebo phenomenon is common and may have potentially negative consequences for the results of clinical treatment and trials. It is therefore important that doctors and medical researchers consider any potential nocebo effect while assessing the treatment effect and try to minimise it through careful choice and phrasing of treatment-related information given to patients.
Sex has been speculated to be a predictor of the placebo and nocebo effect for many years, but whether this holds true or not has rarely been investigated. We utilized a placebo literature database on various aspects of the genuine placebo/nocebo response. In 2015, we had extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine). These meta-analyses were screened for whether sex/gender differences had been noted to contribute to the placebo/nocebo effect: in only 3 such analyses female sex was associated with a higher placebo effect, indicating poor evidence for a contribution of sex to it in RCTs. This was updated with another set of meta-analyses for the current review, but did not change the overall conclusion. The same holds true for 18 meta-analyses investigating adverse event (nocebo) reporting in RCT in the placebo arm of trials. We also screened our database for papers referring to sex/gender and the placebo effect in experimental studies, and identified 28 papers reporting 29 experiments. Their results can be summarized as follows: (a) Despite higher sensitivity of pain in females, placebo analgesia is easier to elicit in males; (b) It appears that conditioning is effective specifically eliciting nocebo effects; (c) Conditioning works specifically well to elicit placebo and nocebo effects in females and with nausea; (d) Verbal suggestions are not sufficient to induce analgesia in women, but work in men. These results will be discussed with respect to the question why nausea and pain may be prone to be responsive to sex/gender differences, while other symptoms are less. Lastly, we will discuss the apparent discrepancy between RCT with low relevance of sex, and higher relevance of sex in specific experimental settings. We argue that the placebo response is predominantly the result of a conditioning (learning) response in females, while in males it predominantly may be generated via (verbal) manipulating of expectancies. In RCT therefore, the net outcome of the intervention may be the same despite different mechanisms generating the placebo effect between the sexes, while in experimental work when both pathways are separated and explicitly explored, such differences may surface.
Placebo effects can be conceptualized as the beneficial effects triggered by the psychosocial treatment context. The nocebo effect is its negative counterpart. Over the last 30 years, the knowledge of placebo and nocebo effects has increased substantially. It has become evident that placebo and nocebo effects are interesting models to understand the intricate mind-body interaction. In addition, they are essential components of any medical setting. The psychological and neurobiological mechanisms underlying these phenomena are specified. In particular, psychological mechanisms are identified as mediators of placebo and nocebo responses; indeed, cognitive and emotional processes such as expectations, self-efficacy desires, anxiety, and somatic focus but also learning mechanisms can enhance or reduce the effectiveness of a medical treatment. Furthermore, the psychosocial context triggers a cascade of neurobiological changes in the brain. The study of these phenomena has important translational implications in the clinical setting.
The term nocebo refers to the worse outcomes or side effects experienced by patients as a result of their negative expectations regarding a treatment. It may distort estimates of treatment effectiveness and safety in both clinical trials and clinical practice; moreover, it may cause discontinuation of therapy or drop out from a trial.
Nocebo effect is evoked by the information given to patients during a clinical consultation or during enrolment into a study, but information available from the media or the Internet may also play an important role. In research settings, a trial design may introduce bias from the nocebo effect. For example, if the non-treatment group is unblinded and aware that they are not receiving any treatment, their treatment expectations are not met, which results in worse outcomes, and subsequently, the problems that the trial was supposed to investigate may be enhanced in the non-treatment arm.
Nocebo effect is common, and its magnitude may be large, but it receives less attention and research focus than the placebo effect. Unlike the placebo effect, which is usually taken into consideration while interpreting treatment results and controlled for in clinical trials, the nocebo effect is under-recognised by clinical researchers as well as clinicians.
It is important to recognise and any potential nocebo effect must be considered while assessing the effect of treatment and should be minimised through careful choice and phrasing of treatment-related information given to the patients.
The investigation of nocebo effects is evolving and a few literature reviews have emerged, however, so far without quantifying such effects. This quantitative systematic review 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 follow 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 = -0.43-4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic studies. In studies where 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 where nocebo effects were induced by verbal suggestions alone (lowest g = 0.64 (-0.25-1.53) and highest g = 0.87 (0.40-1.34)). These findings are similar to those in the placebo literature. Since the magnitude of the nocebo effect is variable and sometimes large, this systematic review demonstrates the importance of minimizing nocebo effects in clinical practice.
Information provided to patients is thought to influence placebo and drug effects. In a prospective, within-subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migraine attacks, each participant received either placebo or Maxalt (10-mg rizatriptan) administered under three information conditions ranging from negative to neutral to positive (told placebo, told Maxalt or placebo, told Maxalt) (N = 459 documented attacks). Treatment order was randomized. Maxalt was superior to placebo for pain relief. When participants were given placebo labeled as (i) placebo, (ii) Maxalt or placebo, and (iii) Maxalt, the placebo effect increased progressively. Maxalt had a similar progressive boost when labeled with these three labels. The efficacies of Maxalt labeled as placebo and placebo labeled as Maxalt were similar. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect. Increasing "positive" information incrementally boosted the efficacy of both placebo and medication during migraine attacks. The benefits of placebo persisted even if placebo was honestly described. Whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of care.
We investigated a possible interaction between topic analgesic treatment and treatment expectation on pain at the behavioral and neuronal level by combining topical lidocaine-prilocaine treatment with an expectancy manipulation in a 2-by-2 within-subject design (open treatment, hidden treatment, placebo, control). 32 healthy subjects received heat pain stimuli on capsaicin pretreated skin and rated their experienced pain during functional magnetic resonance imaging. This allowed us to separate drug- and expectancy-related effects at the behavioral and neuronal level and to test whether they interact during the processing of painful stimuli. Pain ratings were reduced during active treatment and were associated with reduced activity in the anterior insular cortex. Pain ratings were lower in open treatment compared to the hidden treatment and related to reduced activity in the anterior insular cortex, the anterior cingulate cortex, the secondary somatosensory cortex and the thalamus. Testing for an interaction revealed that the expectation effect was significantly larger in the active treatment conditions compared to the no-treatment conditions and was associated to signal changes in the anterior insular cortex, the anterior cingulate cortex and the ventral striatum. In conclusion, this study shows that even in the case of a topic analgesic, expectation interacts with treatment at the level of pain ratings and neuronal responses in placebo-related brain regions. Our results are highly relevant in the clinical context as they show (i) that expectation can boost treatment and (ii) that expectation and treatment are not necessarily additive as assumed in placebo controlled clinical trials.
A clear majority of patients with chronic pain are women; however, it has been surprisingly difficult to determine whether this sex bias corresponds to actual sex differences in pain sensitivity. A survey of the currently available epidemiological and laboratory data indicates that the evidence for clinical and experimental sex differences in pain is overwhelming. Various explanations for this phenomenon have been given, ranging from experiential and sociocultural differences in pain experience between men and women to hormonally and genetically driven sex differences in brain neurochemistry.
The hypothesis put forth is that expectations of treatment effects reduce negative emotions and thereby reduce symptoms, e.g. pain. Negative emotions increase pain, and it is hypothesized that placebos reduce pain by reducing negative emotions, i.e. feelings of nervousness, fear and anxiety. Placebo analgesia has been shown to be mediated via opioid activity, and relaxation increases opioid activity. The placebo acquires its relaxing effect due to verbal information that pain will be reduced, or due to associations between the placebo and the reduction in pain after effective treatment. Thus, the placebo signals that unpleasantness will be less after administration of the placebo. This involves negative reinforcement which is due to activation of a dopaminergic system that has been found to be activated during placebo analgesia and is involved in positive emotions. The nocebo effect of increased pain is, consistent with this model, because of increased fear and anxiety. The new aspect of the presented model is the hypothesis that expectations reduce negative emotions, and that negative reinforcement that involves the dopaminergic reinforcement system should be a contributor to placebo responses.
Physical complaints, such as pain, can be effectively reduced by placebo effects through induction of positive expectations, or increased by nocebo effects through induction of negative expectations. In the present study, verbally induced nocebo and placebo effects on itch were experimentally investigated for the first time. In part 1, the role of verbal suggestions in inducing nocebo effects on itch and pain was investigated. All subjects received the same somatosensory quantitative sensory testing stimuli, that is, mechanical and electrical stimuli and application of histamine, and verbal suggestions to manipulate expectations regarding the stimuli. The suggestions were designed to produce either high expectations for itch (itch nocebo) or pain (pain nocebo) or low expectations for itch (itch nocebo control) or pain (pain nocebo control). Results showed that high itch and pain expectations resulted in higher levels of itch and pain, respectively. When comparing nocebo effects, induced by verbal suggestions, results were more pronounced for itch than for pain. In part 2, verbal suggestions designed to produce a placebo effect on itch (itch placebo) or pain (pain placebo), or neutral suggestions (itch placebo control and pain placebo control) were given regarding a second application of histamine and compared with the first application applied in part 1. Results of placebo effects only showed a significantly larger decrease in itch in the itch placebo condition than in the pain placebo condition. In conclusion, we showed for the first time that nocebo and possibly placebo responses can be induced on itch by verbal suggestions.
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.
The recent introduction of covert administration of treatment to biomedical research has produced some interesting results, with many clinical and ethical implications. Concealed treatment has been used in people with nervous system conditions including pain, anxiety, and Parkinson's disease. The main finding is that when the patient is completely unaware that a treatment is being given, the treatment is less effective than when it is given overtly in accordance with routine medical practice. The difference between open and hidden administrations is thought to represent the placebo component of the treatment, even though no placebo has been given. The decreased effectiveness of hidden treatments indicates that knowledge about a treatment affects outcome and highlights the importance of the patient-provider interaction. In addition, by use of covert administration, the efficacy of some treatments can be assessed without the use of a placebo and associated ethical issues.
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.
Expectation and conditioning are supposed to be the two main psychological mechanisms for inducing a placebo response. Here, we further investigate the effects of both expectation, which was induced by verbal suggestion alone, and conditioning at the level of N1 and N2-P2 components of CO2 laser-evoked potentials (LEPs) and subjective pain reports. Forty-four healthy volunteers were pseudorandomly assigned to one of three experimental groups: Group 1 was tested with verbal suggestion alone, Group 2 was tested with a conditioning procedure, whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the volunteers believe that the treatment was effective, Group 3 was a control group that allowed us to rule out phenomena of sensitization and/or habituation. Pain perception was assessed according to a Numerical Rating Scale (NRS) ranging from 0=no pain sensation to 10=maximum imaginable pain. Both verbal suggestions (Group 1) and conditioning (Group 2) modified the N2-P2 complex, but not the N1 component of LEPs. However, the suggestion-induced LEP changes occurred without subjective perception of pain decrease. Conversely, the N2-P2 amplitude changes that were induced by the conditioning procedure were associated with the subjective perception of pain reduction. Compared to natural history, conditioning produced more robust reductions of LEP amplitudes than verbal suggestions alone. Overall, these findings indicate that prior positive experience plays a key role in maximizing both behavioral and neurophysiological placebo responses, emphasizing that the placebo effect is a learning phenomenon which affects the early central nociceptive processing.
Research shows that placebo analgesia can be induced through social observational learning. Our aim was to replicate and extend this result by studying the effect of the sex of both the model and the subject on the magnitude of placebo analgesia induced by social observational learning. Four experimental (1 through 4) and 2 control (5 and 6) groups were observed: groups 1, 3, and 5 were female; groups 2, 4, and 6 were male. All subjects received pain stimuli of the same intensity preceded by green and red lights. Before receiving pain stimuli, groups 1 and 4 observed a female model and groups 2 and 3 a male model; both models simulated responses to pain stimuli preceded by green lights as less painful than those preceded by red lights. Groups 1 through 4 also rated pain stimuli preceded by green lights as less painful. Further investigation revealed that in fact subjects in experimental groups rated red-associated stimuli as more painful than subjects from control groups who did not observe a model before receiving the same pain stimuli, indicating that nocebo hyperalgesia rather than placebo analgesia was induced. Empathy traits predicted the magnitude of nocebo hyperalgesia. Regardless of the sex of the subject, nocebo hyperalgesia was greater after the male model was observed. The results show that social observational learning is a mechanism that produces placebo effects. They also indicate that the sex of the model plays an important role in this process.
INTRODUCTION: Nocebo effects can be acquired by verbal suggestion but it is unknown whether they can be induced through observational learning and whether they are influenced by factors known to influence pain perception such as pain anxiety or pain catastrophizing. METHOD: Eighty-five female students (22.5 ± 4.4 years) were randomly assigned to one of three conditions. Participants in the control condition (CC) received information that an ointment had no effect on pain perception. Participants in the verbal suggestion condition (VSC) received information that it increased pain sensitivity. Participants in the social observational learning condition (OLC) watched a video in which a model displayed more pain when ointment was applied. Subsequently, all participants received three pressure pain stimuli (60 sec) on each hand. On one hand the ointment was applied prior to the stimulation. Numerical pain ratings were collected at 20-second intervals during pain stimulation. The participants filled in questionnaires regarding pain-related attitudes (PASS, PCS, SSAS). RESULTS: Participants in the OLC showed higher pain ratings with than without ointment. Pain ratings within the CC and the VSC were at the same level with and without ointment. In the VSC, the pain ratings were higher than in the CC with and without ointment. The nocebo response correlated with pain catastrophizing but not with pain anxiety or somatosensory amplification. DISCUSSION: A nocebo response to pressure pain was induced by observational learning but not by verbal suggestion. This finding highlights the importance of investigating the influence of observational learning on nocebo hyperalgesia.
Topical anesthetics remain a powerful, new advance for pain relief prior to cutaneous procedures. They are frequently used by dermatologists to decrease the pain associated with laser pulses, surgical procedures, or soft tissue augmentation. EMLA is the most commonly used agent, however, several new topical anesthetic agents have been released recently that claim increased efficacy and a faster onset of action.
We review and compare the efficacy of several commonly used topical anesthetics and provide a look into the future.
EMLA remains the most widely used topical anesthetic given its proven efficacy and safety by several clinical trials. There has been a recent release of several new topical anesthetic agents with some demonstrating efficacy after a 30-minute application time. A reservoir of anesthetic is located and stored in the upper skin layers during application, providing additional anesthetic benefit 30 minutes after removal. As the options for the practitioner continue to grow, the demand for faster onset, comparative efficacy, and safety trials will continue to be of paramount importance.
Background In order to elucidate placebo and nocebo effects in visceral pain, we analyzed the effects of positive and negative expectations on rectal pain perception, rectal pain thresholds, state anxiety and cortisol responses in healthy women.
Methods Painful rectal distensions were delivered at baseline, following application of an inert substance combined with either positive instructions of pain relief (placebo group, N = 15), negative instructions of pain increase (nocebo group, N = 17), or neutral instructions (control, N = 15). Perceived pain intensity, unpleasantness/aversion and urge-to-defecate, state anxiety and serum cortisol were determined at baseline, immediately following group-specific instructions and on a second study day after the same instructions (test day). Rectal pain thresholds were determined at baseline and on the test day.
Key Results Whereas perceived pain intensity was significantly decreased in the placebo group, the nocebo group revealed significantly increased pain intensity ratings, along with significantly greater anticipatory anxiety on the test day (all P < 0.05 vs controls). Cortisol concentrations were significantly increased in the nocebo group following treatment but not on the test day.
Conclusions & Inferences The experience of abdominal pain can be experimentally increased or decreased by inducing positive or negative expectations. Nocebo effects involve a psychological stress response, characterized by increased anticipatory anxiety. These findings further underscore the role of cognitive and emotional factors in the experience of visceral pain, which has implications for the pathophysiology and treatment of patients with chronic abdominal complaints.
To determine whether there is a sex difference in placebo and ibuprofen analgesia expectancy.
We measured detection and tolerance thresholds for electrically induced pain in the ear lobe in healthy subjects (10 male, 10 female) to study sex differences in expectancy following either ibuprofen 800 mg or placebo in four different expectancy states. Subjects took ibuprofen or placebo in a two-by-two factorial design (the balanced placebo design). We randomly assigned subjects to start in one of the four expectancy states. We analysed the results using analysis of variance for repeated measures with baseline pain as a covariate.
We found no sex difference in baseline pain threshold or tolerance levels. When partitioned by sex and expectancy state, analgesia only occurred in males during positive expectancy states at 2, 3 and 4 h post-placebo, and at 1 and 2 h post-ibuprofen. The time course of analgesic action in males was as expected considering the pharmacokinetic profile of ibuprofen. Our study found that dosages of 800 mg of ibuprofen are ineffective in producing analgesia in women regardless of their expectations. We hypothesize that ibuprofen analgesia is produced by a combination of specific pharmacological effects and a non-specific beta endorphin-mediated placebo effect. Whatever the mechanism responsible for the analgesic response seen in males, this research re-emphasizes the importance of psychological factors in determining drug response. It also shows that these factors can differ between men and women, and thus the contribution of psychological factors on analgesia needs to be seriously re-evaluated.
Placebo analgesia (PA) is one of the most studied placebo effects. Brain imaging studies published over the last decade, using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), suggest that multiple brain regions may play a pivotal role in this process. However, there continues to be much debate as to which areas consistently contribute to placebo analgesia-related networks. In the present study, we used activation likelihood estimation (ALE) meta-analysis, a state-of-the-art approach, to search for the cortical areas involved in PA in human experimental pain models. Nine fMRI studies and two PET studies investigating cerebral hemodynamic changes were included in the analysis. During expectation of analgesia, activated foci were found in the left anterior cingulate, right precentral, and lateral prefrontal cortex and in the left periaqueductal gray (PAG). During noxious stimulation, placebo-related activations were detected in the anterior cingulate and medial and lateral prefrontal cortices, in the left inferior parietal lobule and postcentral gyrus, anterior insula, thalamus, hypothalamus, PAG, and pons; deactivations were found in the left mid- and posterior cingulate cortex, superior temporal and precentral gyri, in the left anterior and right posterior insula, in the claustrum and putamen, and in the right thalamus and caudate body. Our results suggest on one hand that the modulatory cortical networks involved in PA largely overlap those involved in the regulation of emotional processes, on the other that brain nociceptive networks are downregulated in parallel with behavioral analgesia. Hum Brain Mapp, 2011. © 2011 Wiley Periodicals, Inc.
Fear of pain (FOP) and its effect on placebo analgesia was investigated. It was hypothesized that FOP should interfere with placebo-mediated pain inhibition and result in weaker placebo responding in pain intensity, pain unpleasantness, stress, and event-related potentials to contact heat pain. Thirty-three subjects participated in a balanced 2 condition (natural history, placebo)×3 test (pretest, posttest 1, posttest 2) within-subject design, tested on 2 separate days. FOP was measured by the Fear of Pain Questionnaire and subjective stress by the Short Adjective Check List. Placebo effects were found on reported pain unpleasantness and N2 and P2 amplitudes. FOP was related to reduced placebo responding in pain unpleasantness, but this was only evident for the subjects who received the placebo condition on day 1. Subjects who received the placebo condition on day 1 experienced more pretest stress than those who received the placebo condition on day 2 (ie, reversed condition order), and this explained the interaction effect on placebo responding. FOP was related to reduced placebo responding on P2 amplitude, whereas placebo responding on N2 amplitude was unaffected by FOP. Higher placebo responses on N2 and P2 amplitudes were both related to higher placebo analgesic magnitude in pain unpleasantness. In conclusion, increased FOP was found to reduce subjective and electrophysiological placebo analgesic responses.
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.
To examine whether there are gender differences in event-related potential (ERP) responses to painful stimulation after administration of placebo medication; and to investigate whether placebo medication reduces anticipatory stress and if this reduction can explain the placebo analgesic response. Several experimental and clinical studies have shown that males report lower pain compared with females. There are, however, few reports of gender differences in placebo analgesia.
All subjects (n = 33; 17 women) participated in both a natural history and a placebo condition. ERPs were evoked by heat pulses with a peak at 52 °C.
The results showed that pain unpleasantness and the N2/P2 ERP components were reduced in the placebo condition compared with the natural history condition. Only men displayed placebo responses in pain report and in the P2 component. Anticipatory stress was reduced after placebo administration, and the reduction in anticipatory stress was significantly related to the placebo effect on pain. Regression analyses revealed that the interaction of gender by anticipatory stress was significantly related to the mean placebo response, with men responding with lower stress after placebo medication, and larger placebo responses.
A placebo response on pain unpleasantness was observed in men only, and reduced stress after placebo administration was observed in males only. Thus, reduced stress may be a mechanism for placebo responses in pain.
Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.
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.
Recent meta-analyses find various magnitudes of placebo analgesia effects in placebo mechanism trials versus placebo control trials, which have led to debate. To further investigate the magnitude of placebo analgesia in placebo mechanism trials the databases "PubMed", "PsycINFO" and "Web of Science" (2002-2007) were searched with the term "placebo analgesia". Twenty-one articles including 24 studies fulfilled the selection criteria (concerning: mechanisms, control, placebo treatment, randomization and pain measures). The validity of studies was assessed by the authors and effect sizes were calculated via difference scores. The magnitude of placebo analgesia in placebo mechanism studies was large (d=1.00) and about five times larger than placebo analgesia effects in placebo control studies (d=0.15-0.27). Differences in magnitude between the two types of studies appear to result from different types of suggestions given for pain relief. The magnitude of placebo effects was larger in studies that used long-term pain stimuli >20s (d=0.96) as opposed to short-term stimuli (d=0.81) and the largest placebo effects were found in studies wherein hyperalgesia was present (d=1.88). These results replicate our previous finding that placebo analgesic effects are higher in mechanism studies than in placebo control studies. However, since magnitudes of placebo analgesic effects are highly variable it may be valuable to investigate the factors and mechanisms that contribute to this variability as well as differences in magnitudes across types of studies.
To investigate the role of Pavlovian conditioning and expectancy and of gender on the nocebo effects.
Conditioning experiment: Forty-eight healthy male and female volunteers were investigated for 3 days using a standard rotation procedure. Subjects in the experimental group received a salient oral stimulus prior to rotation; subjects in the control group received the stimulus 12 h after rotations on Days 1 and 2; on Day 3, all subjects received the stimulus prior to rotation. Expectancy experiment: Another 48 healthy subjects were rotated 5 x 1 min once only. All subjects received the same oral stimulus immediately prior to rotation; subjects in the experimental group were told that the symptoms might worsen with the stimulus; controls did not receive additional information. In both experiments, symptom rating (SR) and rotation tolerance (RT) were determined.
Conditioning significantly reduced RT (P=.015) and increased SR (P=.024). For both RT and SR, a significant "day x group x gender" effect was found (P=.044; SR: P=.011) indicating that conditioning was more effective in women. Expectancies lowered RT (P=.085) without affecting SR. There was a significant "rotation x gender" interaction on RT (P=.005) indicating that the expectancy was more effective in men.
Women responded stronger to conditioning while men responded to expectancies, but to a lesser degree. It needs to be determined whether this is restricted to nausea-specific conditions or can be generalized across clinical and experimental conditions.
To examine whether reduction of negative emotions and associated autonomic activity could explain placebo analgesia, and to test the effect of experimenter gender on the placebo analgesic response.
Sixty-three (n = 32 females) students participated in a within-subjects design where subjects were tested on two separate days, one day for the experimental condition (placebo) and one day for the natural history condition. In the experimental condition, the participants received capsules containing lactose with information that the capsules were a high dose of a potent painkiller. In the natural history condition, the procedures were identical except that the placebo capsules were not administrated. The experimenters were blinded to the fact that all participants received placebo. Pain was induced by a thermode holding +46 degrees C with duration of 240 seconds to the forearm. Electrocardiogram was measured to obtain data for analysis of heart rate variability. Subjective measurements consisted of pain intensity, pain unpleasantness, stress, arousal, and mood.
The results showed a placebo effect on pain intensity and a concomitant reduction in subjective stress and cardiac activity. Stepwise regressions revealed that reduced subjective stress was the only predictor for the placebo analgesic response. Contrary to our hypothesis, male subjects displayed increased placebo analgesia when a male acted as experimenter.
The results indicate that reduced negative emotional activation could be a mechanism in placebo analgesia and that experimenter gender is probably not systematically related to placebo analgesia.
Hypotheses involving mediation are common in the behavioral sciences. Mediation exists when a predictor affects a dependent variable indirectly through at least one intervening variable, or mediator. Methods to assess mediation involving multiple simultaneous mediators have received little attention in the methodological literature despite a clear need. We provide an overview of simple and multiple mediation and explore three approaches that can be used to investigate indirect processes, as well as methods for contrasting two or more mediators within a single model. We present an illustrative example, assessing and contrasting potential mediators of the relationship between the helpfulness of socialization agents and job satisfaction. We also provide SAS and SPSS macros, as well as Mplus and LISREL syntax, to facilitate the use of these methods in applications.
Describes the development of a mood adjective checklist to measure self-reported stress and arousal. The scale was adapted for British use from one originally constructed by R. E. Thayer (see record
1967-08169-001). When the new scale was administered to 145 British undergraduates, 2 bipolar factors (rather than the 4 monopolar factors found by Thayer) were revealed and labeled Stress and Arousal. Item loadings on these factors are presented. A 2nd study with 72 Ss produced similar factors. Additional support for a 2-factor solution is described. (9 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This paper provides further discussion on the measurement of mood using self-report inventories. It comments on questions raised by Cruickshank (1984) about the structure and use of the stress-arousal checklist developed by Mackay and Cox (Mackay et al., 1978).
In a laboratory experiment, the expected analgesic action of 33% nitrous oxide was reversed by creating the expectancy of heightened awareness of bodily sensations. Pain threshold and tolerance of electrical tooth-pulp stimulation were significantly reduced. Results from a control study gave us a basis for comparison of changes in the verbal expression of pain when nitrous oxide was administered without introducing expectancies beyond those already held by the subjects. Contrasting results from the experimental and control studies confirm the powerful role of mental processes in mediating pain experience.
Administration of the muscle relaxant carisoprodol and placebo was crossed with information that was agonistic or antagonistic to the effect of carisoprodol. It was investigated whether information alone induced physiological and psychological responses, and whether information modified the response to the drug.
Half of the subjects received capsules containing 525 mg carisoprodol together with information that the drug acted in a specific way (Groups Relaxant/C, Stimulant/C, and No Information/C). The other half of the subjects received lactose (Groups Relaxant/L, Stimulant/L, and No Information/L). Dependent variables were blink reflexes and skin conductance responses, subjective measures of tension and sleepiness, and serum carisoprodol and meprobamate concentrations. Recordings were made between 15 and 130 minutes after administration of the capsules.
The Stimulant/L group reported more tension compared with the other two groups, and carisoprodol increased tension even more in the Stimulant/C group. The Relaxant/C group displayed higher levels of carisoprodol serum concentration compared with the other groups that received carisoprodol.
Reported tension was modulated in the direction suggested by the stimulant information. The effect of carisoprodol on tension was also modulated by stimulant information. Increased carisoprodol absorption in the group that received relaxant information could be a mechanism in the placebo response.
We determine whether the addition of heat to topical eutectic mixture of local anesthetic (EMLA) cream shortens the onset time to effective analgesia. We hypothesized that applying EMLA cream for 20 minutes with an external heat pack would be as effective as the standard 60-minute application time.
In this prospective, double-blind study using adult volunteers, research subjects were randomized into groups undergoing either 20 minutes or 60 minutes of EMLA cream application time. Each research subject underwent randomized cream application over both hands and wrists in the following manner: EMLA cream with heat, EMLA cream without heat, placebo with heat, and placebo without heat. Research subjects then underwent a single attempt at intravenous catheterization over each of the 4 sites and scored the degree of pain using a 100-mm visual analog scale.
Seventy-six research subjects were enrolled: 39 were randomized to the 20-minute group, and 37 were randomized to the 60-minute group. EMLA cream applied for 20 minutes with heat (adjusted mean visual analog scale score of 31.9 mm) provided statistically and clinically significantly greater analgesia compared with that seen in the placebo groups with or without heat (46.6 and 46.1 mm, respectively), with estimated differences of -14.6 (95% confidence interval [CI] -21.2 to -8.1) and -14.1 (95% CI -20.8 to -7.3), respectively. However, applying EMLA cream for 60 minutes without heat (16.6 mm) provided better analgesia compared with that seen after 20 minutes of EMLA cream with heat (31.9 mm; estimated difference of -15.4 [95% CI -25.1 to -5.6]).
Applying EMLA cream for 20 minutes with heat provides intermediate analgesia for intravenous catheter placement, although 60 minutes of application time remains superior.
The experiment tested whether the placebo and nocebo responses could be mediated via modulation of stress.
Ischemic pain was induced in healthy volunteers (N = 59). When pain reached "7" on a 10-point scale, two groups of subjects received information that a pain relieving (the Placebo group) or a pain increasing (the Nocebo group) substance was injected. All injections contained physiological saline. A third group received no information and no injection (the Natural History group). Pain ratings and blood samples for analysis of cortisol and beta-endorphin were obtained every 5 minutes after pain equal to seven until the experiment was terminated.
Pain increased in all groups, but there were significantly lower pain ratings in the Placebo group at 15 minutes after the injection, compared with the other two groups. Cortisol increased in all groups, but mostly so in the Nocebo group. Circulating beta-endorphin increased in all groups. Pain-ratings were not correlated with beta-endorphins or cortisol.
A placebo response, ie, a reduced pain level, was seen in the Placebo group at 15 minutes after the injection. The placebo response was not related to stress or to beta-endorphin. Expectation of a pain increase in the Nocebo group led to an increase in cortisol, but the expectation of pain increase and the resultant cortisol increase had no effect on pain.
Unlabelled:
In this randomized, double-blinded, placebo-controlled, crossover trial of 42 human subjects, we examined the speed of onset of cutaneous anesthesia by eutectic mixture of local anesthetics (EMLA) cream after brief (approximately 10-s) pretreatment of the underlying skin with low-frequency (55 kHz) ultrasound. Four treatments were compared: ultrasound pretreatment followed by application of 1 g EMLA or placebo cream for 5 min, 10 min, 15 min, and 60 min without ultrasound pretreatment as positive control. Pain was tested by pricks with a 20 g needle. Pain scores and patient preference for EMLA or placebo cream were measured at each time point. Based on both pain scores and patient preference, cutaneous anesthesia was achieved in the EMLA groups as compared with placebo at all time points. After ultrasound pretreatment and then 5, 10, or 15 min after EMLA cream application, pain scores and overall preference were statistically indistinguishable from EMLA cream application for 60 min (without ultrasound pretreatment). There were no significant adverse effects. Low-frequency ultrasound pretreatment appears to be safe and effective in producing rapid onset of EMLA cream in this model, with results as early as 5 min.
Implications:
A prospective, randomized, double-blinded, placebo-controlled clinical trial demonstrated rapid onset of cutaneous anesthesia by pretreatment of the skin with ultrasound before application of EMLA cream.
Information that a painkiller has been administrated induces an expectancy of reduced pain, and the expectancy has been shown to reduce pain. This is termed placebo analgesia. We hypothesized that an expectancy of reduced pain reduces stress.
The present study (N=84) investigated this hypothesis. To further study the effects of stress and emotions on pain, we provided information about the pain stimulus to half the subjects. Pain was induced by the submaximum tourniquet technique.
Expectations and pain information both decreased pain to the same degree, but independently, and only in males. Lower pain was not related to subjective stress, cortisol, or circulating beta-endorphin. All experimenters were women, and the finding of placebo analgesia only in males fits well with findings that males report less pain to female experimenters.
Placebo analgesia is not related to stress and is influenced by the social context in which pain is recorded.
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.
Prior work indicates that exposure to fear-inducing shock inhibits finger-withdrawal to radiant heat in humans (hypoalgesia), whereas anxiety induced by threat of shock enhances reactivity (hyperalgesia; Pain 84 (2000) 65-75). Although finger-withdrawal latencies are thought to reflect changes in pain sensitivity, additional measures of pain are needed to determine whether pain perception is altered. The present study examined the impact of negative affect on visual analog scale (VAS) ratings of fixed duration thermal stimuli. One hundred twenty-seven male and female human subjects were randomly assigned to one of three emotion-induction conditions: (1) negative affect induced by exposure to three brief shocks; (2) negative affect elicited by the threat of shock without presentation; and (3) neutral affect, with no intervention. VAS ratings were tested before and after emotion-induction. Results suggest that both negative affect manipulations reduced pain. Manipulation checks indicated that the emotion-induction treatments induced similar levels of fear but with different arousal levels. Potential mechanisms for affect induced changes in pain are discussed.
The nocebo effect consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Here we show that nocebo suggestions, in which expectation of pain increase is induced, are capable of producing both hyperalgesic and allodynic responses. By extending previous findings on the placebo effect, we investigated the role of learning in the nocebo effect by means of a conditioning procedure. To do this, verbal suggestions of pain increase were given to healthy volunteers before administration of either tactile or low-intensity painful electrical stimuli. This nocebo procedure was also carried out after a pre-conditioning session in which two different conditioned visual stimuli were associated to either pain or no-pain. Pain perception was assessed by means of a Numerical Rating Scale raging from 0=tactile to 10=maximum imaginable pain. We found that verbal suggestions alone, without prior conditioning, turned tactile stimuli into pain as well as low-intensity painful stimuli into high-intensity pain. A conditioning procedure produced similar effects, without significant differences. Therefore, in contrast to placebo analgesia, whereby a conditioning procedure elicits larger effects compared to verbal suggestions alone, learning seems to be less important in nocebo hyperalgesia. Overall, these findings indicate that, by defining hyperalgesia as an increase in pain sensitivity and allodynia as the perception of pain in response to innocuous stimulation, nocebos can indeed produce both hyperalgesic and allodynic effects. These results also suggest that learning is not important in nocebo hyperalgesia compared to placebo analgesia.
The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil Sex differences in analgesic response to ibuprofen are influenced by expectancy: a randomized, crossover, balanced placebo-designed study
- U Bingel
- V Wanigasekera
- K Wiech
- Ni Mhuircheartaigh
- R Lee
- Mc Ploner
- M Tracey
- I Carmody
Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC,
Ploner M, Tracey I. The effect of treatment expectation on drug efficacy:
imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med
2011;3:70ra14.
[7] Butcher BE, Carmody JJ. Sex differences in analgesic response to
ibuprofen are influenced by expectancy: a randomized, crossover,
balanced placebo-designed study. Eur J Pain 2012;16:1005–13.
The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil
- U Bingel
- V Wanigasekera
- K Wiech
- Ni Mhuircheartaigh
- R Lee
- M C Ploner
- M Tracey
Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, Tracey I.
The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of
the opioid remifentanil. Sci Transl Med 2011;3(70):70ra14.
Cognitive reversal of expected nitrous oxide analgesia for acute pain.
- Dworkin