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
Meulen, C. van der; Stadt, L.A. van de; Kroon, F.P.B.; Kortekaas, M.C.; Boonen, A.E.R.C.H.; Bohringer, S.; ... ; Kloppenburg, M. 2022
Background: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life ... Show moreBackground: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life (HR-QoL) and response to anti-inflammatory treatment of neuropathic-like pain in inflammatory hand OA. Methods: Data were analysed from a 6-week, randomized, double-blind, placebo-controlled trial investigating prednisolone treatment in 92 patients with painful inflammatory hand OA. Neuropathic-like pain was measured with the painDETECT questionnaire. Associations between baseline characteristics and baseline neuropathic-like pain were analysed with ordinal logistic regression, association of baseline neuropathic-like pain symptoms with baseline HR-QoL with linear regression, painDETECT and visual analogue scale (VAS) change from baseline to week 6 and interaction of painDETECT with prednisolone efficacy on VAS pain change from baseline to week 6 with generalized estimating equations (GEE). Results: Of 91 patients (79% female, mean age 64) with complete painDETECT data at baseline, 53% were unlikely to have neuropathic-like pain, 31% were indeterminate and 16% were likely to have neuropathic-like pain. Neuropathic-like pain was associated with female sex, less radiographic damage and more comorbidities. Patients with neuropathic-like pain had lower HR-QoL (PCS-6.5 [95% CI -10.4 to -2.6]) than those without. Neuropathic-like pain symptoms remained under prednisolone treatment and no interaction was seen between painDETECT and prednisolone efficacy on VAS pain. Conclusions: In this study, 16% of inflammatory hand OA patients had neuropathic-like pain. They were more often female, had more comorbidities and had lower QoL than those without. Neuropathic-like pain symptoms remained despite prednisolone treatment and did not seem to affect the outcome of prednisolone treatment. Significance: Pain is the dominant symptom in hand OA, with an unclear aetiology. In this study, we found that neuropathic-like pain may play a role in hand OA, that it showed associations with female sex, younger age and more comorbidities and that it lowered health-related quality of life in hand OA. Neuropathic-like pain in hand OA seems resistant to prednisolone therapy but did not seem to interfere with the treatment of inflammatory pain with prednisolone. Show less
Pozo-Rosich, P.; Gil-Gouveia, R.; Donnet, A.; Poole, A.C.; Gendolla, A.; Afridi, S.; ... ; Tassorelli, C. 2021
Background Clinical guidelines agree that preventive treatment should be considered in patients with uncontrolled migraine despite acute medications or patients with >= 4 migraine days per month... Show moreBackground Clinical guidelines agree that preventive treatment should be considered in patients with uncontrolled migraine despite acute medications or patients with >= 4 migraine days per month. However, the criteria to define the effectiveness of treatment and the factors that inform the decision to (dis)continue it are not clearly defined in clinical practice. Methods Overall, 148 healthcare practitioners from five European countries completed a two-wave questionnaire. The Steering Committee defined a simulated set of 108 migraine patient profiles based on the combination of five factors (frequency of the attacks, intensity of the attacks, use of acute migraine medications, patient perception and presence/absence of tolerable side effects). These profiles were used in a Delphi survey among European neurologists to identify the criteria that should be used to decide treatment response and continuation using a conjoint analysis approach. Results Consensus was reached for 82/108 (76%) of profiles regarding treatment response, and for 86/108 (80%) regarding treatment continuation. Multivariable logistic regression analysis showed that a >= 50% reduction in the use of acute migraine medications and positive patient's perception of treatment were the most important factors that lead to the decision of continuing (combined factors, OR = 18.3, 95% CI 13.4-25.05). Conclusions This survey identifies two relevant outcome measures: one objective (use of acute migraine treatment medications) and one subjective (positive patient perception) that guide the clinician decision to continue preventive treatment in migraine patients. Significance In clinical practice, criteria to define the effectiveness of migraine preventive treatment and factors that guide treatment stop or continuation are not clearly defined. In this simulated clinical setting study, a reduction in the use of acute migraine medications was the factor associated with preventive treatment effectiveness definition. This study also revealed that factors strongly associated with the decision of treatment continuation in real life are the acute migraine medications use and a positive patient's perception of treatment effectiveness. Show less
Background Vocalization is often used to assess pain, sometimes combined with other behaviours such as facial expressions. Contrary to facial expressions, however, for vocalization, there is little... Show moreBackground Vocalization is often used to assess pain, sometimes combined with other behaviours such as facial expressions. Contrary to facial expressions, however, for vocalization, there is little evidence available on the association with pain. The aim of this systematic review was to critically analyse the association between vocalization and pain, to explore if vocalizations can be used as a "stand-alone" indicator for pain. Methods The search was performed according to the Prisma Guidelines for systematic reviews and meta-analysis. The following terms were used: "Pain Measurement," "Vocalization" and "Verbalization." The study population included verbal and non-verbal individuals, including older people and children. The search was performed in three different databases: PubMed, Embase and CINAHL. A total of 35 studies were selected for detailed investigation. Quality assessments were made using two grading systems: Grading of Recommendations Assessment Development and Evaluation system and the Newcastle-Ottawa scale. Results An association between vocalization and pain was found in most studies, particularly when different types of vocalizations were included in the investigation. Different types of vocalization, but also different types of pain, shape this association. The association is observed within all groups of individuals, although age, amongst others, may have an influence on preferred type of vocalization. Conclusions There is an association between vocalization and pain. However, vocalization as a "stand-alone" indicator for pain indicates only a limited aspect of this multifactorial phenomenon. Using vocalization as an indicator for pain may be more reliable if other pain indicators are also taken into account. Significance Vocalizations are frequently used in pain scales, although not yet thoroughly investigated as a "single indicator" for pain, like, e.g. facial expression. This review confirms the role of vocalizations in pain scales, and stresses that vocalizations might be more reliable if used in combination with other pain indicators. Show less
Kunz, M.; Waal, M.W.M. de; Achterberg, W.P.; Gimenez-Llort, L.; Lobbezoo, F.; Sampson, E.L.; ... ; Lautenbacher, S. 2020
Background: Over the last decades, a considerable number of observational scales have been developed to assess pain in persons with dementia. The time seems ripe now to build on the knowledge and... Show moreBackground: Over the last decades, a considerable number of observational scales have been developed to assess pain in persons with dementia. The time seems ripe now to build on the knowledge and expertize implemented in these scales to form an improved, "best-of" meta-tool. The EU-COST initiative "Pain in impaired cognition, especially dementia" aimed to do this by selecting items out of existing observational scales and critically re-assessing their suitability to detect pain in dementia. This paper reports on the final phase of this collaborative task.Methods: Items from existing observational pain scales were tested for "frequency of occurrence (item difficulty)," "reliability" and "validity." This psychometric testing was carried out in eight countries, in different healthcare settings, and included clinical as well as experimental pain conditions.Results: Across all studies, 587 persons with dementia, 27 individuals with intellectual disability, 12 Huntington's disease patients and 59 cognitively healthy controls were observed during rest and movement situations or while receiving experimental pressure pain, respectively. The psychometric outcomes for each item across the different studies were evaluated within an international and multidisciplinary team of experts and led a final selection of 15 items (5x facial expressions, 5x body movements, 5x vocalizations).Conclusions: The final list of 15 observational items have demonstrated psychometric quality and clinical usefulness both in their former scales and in the present international evaluation; accordingly, they qualified twice to form a new internationally agreed-on meta-tool for Pain Assessment in Impaired Cognition, the PAIC-15 scale. Significance: Using a meta-tool approach by building on previous observational pain assessment scales and putting the items of these scales through rigorous empirical testing (using experimental as well as clinical pain studies in several European countries), we were able to identify the best items for pain assessment in individuals with impaired cognition. These selected items form the novel PAIC15 scale (pain assessment in impaired cognition, 15 items). Show less
Donk, T. van de; Velzen, M. van; Dahan, A.; Niesters, M. 2019
Background Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB)... Show moreBackground Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB) model is a model for inflammatory pain in which three times the minimal erythema dose (3MED) is typically applied to induce sensitization. Based on reports of long-lasting postinflammatory hyperpigmentation (PIH) associated with 3MED, it was decided to investigate the prevalence of PIH among subjects who were previously exposed to 3MED at our research centre. In addition, re-evaluation of the UVB inflammation model using a reduced exposure paradigm (2MED) was performed in healthy subjects. Methods In the first study, all 142 subjects previously exposed to 3MED UVB were invited for a clinical evaluation of PIH. In the second study, 18 healthy subjects were exposed to 2MED UVB, and heat pain detection threshold (PDT) and PIH were evaluated. Results In total, 78 of the 142 subjects responded. The prevalence of PIH among responders was 53.8%. In the second study, we found a significant and stable difference in PDT between UVB-exposed and control skin 3 hr after irradiation; 13 hr post-irradiation, the least squares mean estimate of the difference in PDT ranged from -2.6 degrees C to -4.5 degrees C (p < 0.0001). Finally, the prevalence of PIH was lower in the 2MED group compared to the 3MED group. Conclusions The 3MED model is associated with a relatively high prevalence of long-lasting PIH. In contrast, 2MED exposure produces stable hyperalgesia and has a lower risk of PIH and is therefore recommended for modelling inflammatory pain. Significance Postinflammatory hyperpigmentation is an unwanted long-term side effect associated with the UVB inflammation model using the 3x minimal erythema dose (3MED) paradigm. In contrast, using a 2MED paradigm results in hyperalgesia that is stable for 36 hr and has a lower risk of inducing postinflammatory hyperpigmentation. Show less
BACKGROUND: Although reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the... Show moreBACKGROUND: Although reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the reproducibility of evoked pain models involving human subjects. Here, we studied the reproducibility of a battery of evoked pain models for demonstrating the analgesic effects of two analgesic compounds. METHODS: A total of 81 healthy subjects participated in four studies involving a battery of evoked pain tests in which mechanical, thermal and electrical stimuli were used to measure pain detection and tolerance thresholds. Pharmacodynamic outcome variables were analysed using a mixed model analysis of variance, and a coefficient of variation was calculated by dividing the standard deviation by the least squares means. RESULTS: A total of 76 subjects completed the studies. After being administered pregabalin, the subjects' pain tolerance thresholds in the cold pressor and pressure stimulation tests were significantly increased compared to the placebo group. Moreover, the heat pain detection threshold in Show less
Donk, T. van de; Velzen, M. van; Dahan, A.; Niesters, M. 2019
Background: Tapentadol is a centrally acting analgesic with μ-agonistic activity combined with noradrenaline reuptake inhibition. Its mechanism of action relies on improvement of descending pain... Show moreBackground: Tapentadol is a centrally acting analgesic with μ-agonistic activity combined with noradrenaline reuptake inhibition. Its mechanism of action relies on improvement of descending pain inhibition. In the current study, tapentadol’s ability to enhance conditioned pain modulation (CPM, an experimental measure of descending pain inhibition) was evaluated in fibromyalgia patients with absent or reduced CPM responses.Methods: A total of 34 fibromyalgia patients completed this double-blind trial. Patients were randomized to receive treatment with tapentadol sustained-release or placebo for a 3-month period with 1-month follow-up. At baseline the cornea nerve fiber state (CNFS) was quantified to determine the presence of nerve fiber pathology and assess its value in the prediction of the analgesic response.Results: Tapentadol significantly increased CPM responses during treatment with an average increase from baseline of 20.5 ± 12.5% (tapentadol) versus 3.0 ± 11.2% (placebo; p = 0.042). No treatment effect was observed for the absolute pain scores, however analgesia responder rate analyses demonstrated a treatment effect in favor of tapentadol. Pain relief (a reduction in pain score ³ 30%) was predicted by the presence of a normal CNFS (p = 0.035). Patients with an abnormal CNFS had no analgesic effect from tapentadol despite an increase in CPM.Conclusions: In chronic pain patients with fibromyalgia, the increase in endogenous pain inhibition by tapentadol was translated into analgesia in patients with a normal CNFS. In those with abnormal CNFS, tapentadol treatment was without analgesic effect. Show less
BACKGROUND: Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB)... Show moreBACKGROUND: Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB) model is a model for inflammatory pain in which three times the minimal erythema dose (3MED) is typically applied to induce sensitization. Based on reports of long-lasting postinflammatory hyperpigmentation (PIH) associated with 3MED, it was decided to investigate the prevalence of PIH among subjects who were previously exposed to 3MED at our research centre. In addition, re-evaluation of the UVB inflammation model using a reduced exposure paradigm (2MED) was performed in healthy subjects. METHODS: In the first study, all 142 subjects previously exposed to 3MED UVB were invited for a clinical evaluation of PIH. In the second study, 18 healthy subjects were exposed to 2MED UVB, and heat pain detection threshold (PDT) and PIH were evaluated. RESULTS: In total, 78 of the 142 subjects responded. The prevalence of PIH among responders was 53.8%. In the second study, we found a significant and stable difference in PDT between UVB-exposed and control skin 3 hr after irradiation; 13 hr post-irradiation, the least squares mean estimate of the difference in PDT ranged from -2.6 degrees C to -4.5 degrees C (p < 0.0001). Finally, the prevalence of PIH was lower in the 2MED group compared to the 3MED group. CONCLUSIONS: The 3MED model is associated with a relatively high prevalence of long-lasting PIH. In contrast, 2MED exposure produces stable hyperalgesia and has a lower risk of PIH and is therefore recommended for modelling inflammatory pain. SIGNIFICANCE: Postinflammatory hyperpigmentation is an unwanted long-term side effect associated with the UVB inflammation model using the 3x minimal erythema dose (3MED) paradigm. In contrast, using a 2MED paradigm results in hyperalgesia that is stable for 36 hr and has a lower risk of inducing postinflammatory hyperpigmentation. Show less
