This study investigated for the first time the effects of individual and combined application of 3 learning techniques (verbal suggestions, classical conditioning, and observational learning) on... Show moreThis study investigated for the first time the effects of individual and combined application of 3 learning techniques (verbal suggestions, classical conditioning, and observational learning) on placebo analgesia and extinction.Healthy participants (N = 206) were assigned to 8 different groups in which they were taught through either a verbal suggestion, a conditioning paradigm, a video observing someone, or any combination thereof that a placebo device (inactive transcutaneous electric nerve stimulation [TENS]) was capable of alleviating heat pain, whereas one group did not (control). Placebo analgesia was quantified as the within-group difference in experienced pain when the placebo device was (sham) 'activated' or 'inactivated' during equal pain stimuli, and compared between groups.Placebo analgesia was induced in groups with 2 or 3 learning techniques. Significantly stronger placebo analgesia was induced in the combination of all 3 learning techniques as compared to the individual learning techniques or control condition, underlining the additional contribution of 3 combined techniques. Extinction did not differ between groups. Furthermore, pain expectancies, but not state anxiety or trust, mediated placebo analgesia.Our findings emphasize the added value of combining 3 learning techniques to optimally shape expectancies that lead to placebo analgesia, which can be used in experimental and clinical settings. Perspective: This unique experimental study compared the individual versus combined effects of 3 important ways of learning (verbal suggestions, classical conditioning, and observational learning) on expectation-based pain relief. The findings indicate that placebo effects occurring in clinical practice could be optimally strengthened if healthcare providers apply these techniques in combination.(R) 2023 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Nocebo effects are adverse treatment outcomes that are not ascribed to active treatment components. Potentially, their magnitude might be higher in patients with chronic pain compared to healthy... Show moreNocebo effects are adverse treatment outcomes that are not ascribed to active treatment components. Potentially, their magnitude might be higher in patients with chronic pain compared to healthy controls since patients likely experience treatment failure more frequently. The current study investigated group differences in the induction and extinction of nocebo effects on pressure pain at baseline (N = 69) and 1-month follow-up (N = 56) in female patients with fibromyalgia and matched healthy controls. Nocebo effects were first experimentally induced via classical conditioning combined with instructions on the pain-increasing function of a sham transcutaneous electrical nerve stimulation device, then decreased via extinction. One month later, the same procedures were repeated to explore their stability. Results suggest that nocebo effects were induced in the healthy control group during baseline and follow-up. In the patient group, nocebo effects were only induced during follow-up, without clear group differences. Extinction was only observed during baseline in the healthy control group. Further comparisons of nocebo effects and extinction indicated no significant changes across sessions, possibly suggesting their overall magnitudes were stable over time and across groups. In conclusion, contrary to our expectations, patients with fibromyalgia did not have stronger nocebo hyperalgesia; instead, they might be less responsive to nocebo manipulations than healthy controls. Show less
Nocebo effects on pain are widely thought to be driven by negative expectations. This suggests that anticipatory processing, or some other form of top-down cognitive activity prior to the... Show moreNocebo effects on pain are widely thought to be driven by negative expectations. This suggests that anticipatory processing, or some other form of top-down cognitive activity prior to the experience of pain, takes place to form sensory-augmenting expectations. However, little is known about the neural markers of anticipatory processing for nocebo effects. In this event-related potential study on healthy participants (n = 42), we tested whether anticipatory processing for classically conditioned nocebo-augmented pain differed from pain without nocebo augmentation using stimulus preceding negativity (SPN), and Granger Causality (GC). SPN is a slow-wave ERP component thought to measure top-down processing, and GC is a multivariate time series analysis used to measure functional connectivity between brain regions. Fear of pain was assessed with the Fear of Pain Questionnaire-III and tested for correlation with SPN and GC metrics. We found evidence that both anticipatory processing measured with SPN and functional connectivity from frontal to temporoparietal brain regions measured with GC were increased for nocebo pain stimuli relative to control pain stimuli. Other GC node pairs did not yield significant effects, and a lag in the timing of nocebo pain stimuli limited interpretation of the results. No correlations with trait fear of pain measured after the conditioning procedure were detected, indicating that while differences in neural activity could be detected between the anticipation of nocebo and control pain trials, they likely were not related to fear. These results highlight the role that top-down processes play in augmenting sensory perception based on negative expectations before sensation occurs. Show less
Objectives:The current paper explores the psychological predictors of nocebo hyperalgesia and whether the reduction of nocebo hyperalgesia can be predicted by susceptibility to nocebo hyperalgesia... Show moreObjectives:The current paper explores the psychological predictors of nocebo hyperalgesia and whether the reduction of nocebo hyperalgesia can be predicted by susceptibility to nocebo hyperalgesia and psychological characteristics. Methods:Nocebo effects on pressure pain were first experimentally induced in 83 healthy female participants through conditioning with open-label instructions about the pain-worsening function of a sham TENS device to assess susceptibility to nocebo hyperalgesia. Participants were then randomized to 1 out of 2 nocebo-reduction conditions (counterconditioning/extinction) or to continued nocebo-conditioning (control), each combined with open-label instructions about the new sham device function. Dispositional optimism, trait and state anxiety, pain catastrophizing, fear of pain, and body vigilance were assessed at baseline. Results:The results showed that lower optimism and higher trait anxiety were related to a stronger induction of nocebo hyperalgesia. Moreover, a stronger induction of nocebo hyperalgesia and higher trait anxiety predicted a larger nocebo reduction across interventions. Also, nocebo hyperalgesia and optimism moderated the effects of the nocebo-reduction interventions, whereby larger nocebo hyperalgesia and lower optimism were associated with a larger nocebo reduction after counterconditioning, compared with control, and also extinction for larger nocebo hyperalgesia. Discussion:Our findings suggest that open-label conditioning leads to stronger nocebo hyperalgesia when trait anxiety is high and dispositional optimism is low, while these psychological characteristics, along with larger nocebo hyperalgesia, also predict open-label counterconditioning to be an effective nocebo-reduction strategy. Susceptibility to nocebo hyperalgesia, trait anxiety, and dispositional optimism might be indicators of a flexible pain regulatory system. Show less
Karacaoglu, M.; Meijer, S.; Peerdeman, K.J.; Dusseldorp, E.M.L.; Veldhuijzen, D.S.; Middendorp, H. van; Evers, A.W.M. 2023
BackgroundNocebo effects can adversely affect the experience of physical symptoms, such as pain and itch. Nocebo effects on itch and pain have shown to be induced by conditioning with thermal heat... Show moreBackgroundNocebo effects can adversely affect the experience of physical symptoms, such as pain and itch. Nocebo effects on itch and pain have shown to be induced by conditioning with thermal heat stimuli and reduced by counterconditioning. However, open-label counterconditioning, in which participants are informed about the placebo content of the treatment, has not been investigated, while this can be highly relevant for clinical practice. Furthermore, (open-label) conditioning and counterconditioning has not been investigated for pain modalities relevant to musculoskeletal disorders, such as pressure pain. MethodsIn a randomized controlled trial, we investigated in 110 healthy female participants whether nocebo effects on pressure pain combined with open-label verbal suggestions can be (1) induced via conditioning and (2) reduced via counterconditioning. Participants were allocated to either a nocebo- or sham-conditioning group. Next, the nocebo group was allocated to either counterconditioning, extinction or continued nocebo conditioning; sham conditioning was followed by placebo conditioning. ResultsNocebo effects were significantly larger after nocebo conditioning than sham conditioning (d = 1.27). Subsequently, a larger reduction of the nocebo effect was found after counterconditioning than after extinction (d = 1.02) and continued nocebo conditioning (d = 1.66), with effects similar to placebo conditioning (following sham conditioning). ConclusionsThese results show that (counter)conditioning combined with open-label suggestions can modulate nocebo effects on pressure pain, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders, particularly for musculoskeletal disorders. SignificanceFew studies have investigated the efficacy counterconditioning to reduce nocebo effects. Whereas typically deceptive procedures are used, these are not ethically appropriate for use in clinical practice. The current study demonstrates that open-label counterconditioning in a pain modality relevant for many chronic pain conditions may be a promising new strategy for reducing nocebo effects in a non-deceptive and ethical manner, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders. Show less
Learning and negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. Here, we examined how a targeted pharmacological manipulation of learning would... Show moreLearning and negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. Here, we examined how a targeted pharmacological manipulation of learning would impact nocebo responses and their brain correlates. Participants received either a placebo (n = 27) or a single 80 mg dose of d-cycloserine (a partial NMDA receptor agonist; n = 23) and underwent fMRI. Behavioral conditioning and negative suggestions were used to induce nocebo responses. Participants underwent pre-conditioning outside the scanner. During scanning, we first delivered baseline pain stimulations, followed by nocebo acquisition and extinction phases. During acquisition, high intensity thermal pain was paired with supposed activation of sham electrical stimuli (nocebo trials), whereas moderate pain was administered with inactive electrical stimulation (control trials). Nocebo hyperalgesia was induced in both groups (p < 0.001). Nocebo magnitudes and brain activations did not show significant differences between d-cycloserine and placebo. In acquisition and extinction, there were significantly increased activations bilaterally in the amygdala, ACC, and insula, during nocebo compared to control trials. Nocebo acquisition trials also showed increased vlPFC activation. Increased opercular activation differentiated nocebo-augmented pain aggravation from baseline pain. These results support the involvement of integrative cognitive-emotional processes in nocebo hyperalgesia. Show less
BackgroundNocebo and placebo effects, i.e., adverse or beneficial treatment effects, respectively, putatively due to expectancies can modulate pain and itch. These effects can generalize within the... Show moreBackgroundNocebo and placebo effects, i.e., adverse or beneficial treatment effects, respectively, putatively due to expectancies can modulate pain and itch. These effects can generalize within the pain or itch modality. Predicting the induction and generalization of these effects can be helpful in clinical practice. This study aims to investigate whether psychological characteristics related to the fear-avoidance model predict the induction and generalization of nocebo and placebo effects on pain and itch in young healthy participants. MethodsData from two previous experiments were analyzed. In Experiment 1, we induced nocebo and placebo effects on heat pain and tested generalization to pressure pain and to cowhage-evoked itch (n = 33 in a nocebo group, n = 32 in a placebo group). In Experiment 2, we induced nocebo effects on cowhage-evoked itch and tested generalization to mechanical itch and to mechanical touch (n = 44). Potential predictors were anxiety- and stress symptoms, attention to pain/itch, and pain/itch catastrophizing. Multiple regression analyses were performed. ResultsFor nocebo effects, none of the individual psychological characteristics significantly predicted induction of nocebo effects nor their generalization. For placebo effects, only less stress symptoms, lower attention to pain, and higher pain catastrophizing weakly predicted a stronger generalization of placebo effects from heat pain to pressure pain. ConclusionThe tested psychological characteristics may not play an important role in the induction and generalization of nocebo and placebo effects in healthy individuals. However, firm conclusions cannot be drawn with the current sample. Future studies should validate findings in larger and more diverse samples. Show less
Meijer, S.; Middendorp, H. van; Peerdeman, K.J.; Evers, A.W.M. 2022
Persistent physical symptoms have a high prevalence and a large impact for patients and society. To date, treatment effects for these symptoms are often limited. Nocebo effects (i.e., negative... Show morePersistent physical symptoms have a high prevalence and a large impact for patients and society. To date, treatment effects for these symptoms are often limited. Nocebo effects (i.e., negative outcomes that are not attributable to active treatment components) have a substantial influence on treatment success and can be established via learning through classical conditioning. Therefore, interventions aimed at reducing nocebo effects by means of counterconditioning, in which an alternative association (inhibiting the previous association) is learned, could be a promising method for improving physical symptoms. In experimental studies, counterconditioning has been shown promising in reducing experimentally-induced nocebo effects on pain and itch. Application of counterconditioning procedures to reduce nocebo effects on clinical symptoms has yet to be researched. This paper provides a protocol of a 6-week counterconditioning intervention aimed at reducing nocebo effects and clinical pain in patients with fibromyalgia. A study in patients with fibromyalgia is proposed to examine the feasibility and potential effectiveness of this counterconditioning intervention as a novel treatment method for reducing nocebo effects and generalization to clinical pain symptoms. Results can help design an optimized treatment protocol for reducing nocebo effects, based on the experiences of participants and the first indications of treatment efficacy. Show less
Pain and other somatosensory sensations, such as itch, can be effectively decreased by placebo effects and increased by nocebo effects. There are indications that placebo effects on pain generalize... Show morePain and other somatosensory sensations, such as itch, can be effectively decreased by placebo effects and increased by nocebo effects. There are indications that placebo effects on pain generalize to other sensations and that nocebo effects generalize within itch modalities. However, it has not yet been investigated whether learned effects can generalize within pain stimulus modalities or from pain to itch. Our aims were to test whether placebo and nocebo effects can generalize within pain modalities, ie, from heat pain to pressure pain, and across somatosensory sensations with psychophysiological similarities, ie, from heat pain to cowhage-evoked itch. For this purpose, 65 healthy participants were randomized to either a placebo or nocebo group. All participants first underwent a conditioning and verbal suggestion procedure with heat pain stimuli. Subsequently, responses to heat pain, pressure pain, and cowhage-evoked itch stimuli were tested. Results showed altered levels of heat and pressure pain with the conditioned cue in both placebo and nocebo groups in the expected directions, but no significant difference in itch in both groups. In conclusion, placebo and nocebo effects on pain may generalize within but not across stimulus modalities. This study provides a novel perspective on the role that response generalization plays in physical symptoms. Show less
Nocebo effects, that is, negative treatment outcomes due to negative expectancies, can increase itch. Moreover, indirect evidence has shown that nocebo hyperknesis can generalize to another itch... Show moreNocebo effects, that is, negative treatment outcomes due to negative expectancies, can increase itch. Moreover, indirect evidence has shown that nocebo hyperknesis can generalize to another itch modality. Knowledge on response generalization can help to prevent and decrease negative effects. The aims of this study were to investigate (1) the efficacy of inducing nocebo effects on cowhage-evoked itch via verbal suggestions and (2) whether these effects can generalize to (2a) mechanically evoked touch and (2b) mechanically evoked itch. Forty-four healthy participants watched a video suggesting that a nocebo solution increases cowhage-evoked itch and that a control solution does not affect itch. Subsequently, cowhage, mechanical itch, and mechanical touch stimuli were applied. Nocebo effects were measured as the difference in both mean and peak of the outcomes itch and urge to scratch between nocebo and control trials. Main analyses revealed significant nocebo effects on mean and peak itch for all stimuli. For urge to scratch, a significant nocebo effect was only observed for mechanical touch (peak). As mechanical stimuli did not induce pure sensations as planned, posthoc sensitivity analyses were run for mechanical stimuli that individually induced either touch or itch at baseline. These analyses showed similar results for generalization to mechanical itch, but generalization to mechanical touch was non-significant. This study showed that merely verbal suggestion can induce nocebo effects on cowhage-evoked itch and that these effects can generalize to another itch modality. Future studies may examine how to prevent negative experiences from generalizing to subsequent encounters. Show less
