Psychobiological Mechanisms Underlying Chronic Pain
- Conditions
- Pain, ChronicFibromyalgiaChronic Pain, Widespread
- Interventions
- Registration Number
- NCT04674670
- Lead Sponsor
- susanne becker
- Brief Summary
Pain is a powerful motivator of behavior and it is more than the perception of nociceptive input. It is a complex experience that comprises different components: sensory discriminative, emotional-motivational and cognitive components. In chronic pain, a negative hedonic shift has been proposed that is characterized by disproportionally increased emotional-motivational compared to sensory-discriminative pain components. Such a negative hedonic shift is mirrored in a high comorbidity of chronic pain with affective disorders like depression and anxiety. However, the neurobiological mechanisms underlying such a negative hedonic shift i remain elusive. Animal work suggests an involvement of neuroinflammation, caused by chronic pain, which in turn is related to impaired release of the neurotransmitter dopamine. In line with this observation, impaired dopamine functioning has been described in chronic pain. Importantly, dopamine acts also as a neuromodulator, regulating functional connectivity between brain regions. Therefore, dysfunctional dopamine in chronic pain, possibly caused by neuroinflammation, might lead to altered blood oxygen level dependent (BOLD) response and functional connectivity. Correspondingly, altered functional connectivity in fronto-striatal brain networks has been shown to be predictive of transition from subacute to chronic pain. The aim of this study is to investigate the psychobiological mechanisms underlying the negative hedonic shift in chronic pain with a focus on the role of dopamine in functional connectivity of fronto-striatal brain networks, BOLD response of frontostriatal regions and their relation to heightened emotional-motivational pain processing.
- Detailed Description
Pain is a powerful motivator of behavior and it is more than the perception of nociceptive input. It is a complex experience that comprises different components: sensory discriminative, emotional-motivational and cognitive components. In chronic pain, a negative hedonic shift has been proposed that is characterized by disproportionally increased emotional-motivational compared to sensory-discriminative pain components. Such a negative hedonic shift is mirrored in a high comorbidity of chronic pain with affective disorders like depression and anxiety. However, the neurobiological mechanisms underlying such a negative hedonic shift remain elusive. Animal work suggests an involvement of neuroinflammation, caused by chronic pain, which in turn is related to impaired release of the neurotransmitter dopamine. In line with this observation, impaired dopamine functioning has been described in chronic pain. Importantly, dopamine acts also as a neuromodulator, regulating functional connectivity between brain regions. Therefore, dysfunctional dopamine in chronic pain, might lead to altered functional connectivity. Correspondingly, altered functional connectivity in fronto-striatal brain networks has been shown to be predictive of transition from subacute to chronic pain. The aim of this study is to investigate the psychobiological mechanisms underlying the negative hedonic shift in chronic pain with a focus on the role of dopamine in functional connectivity of fronto-striatal brain networks, BOLD response of frontostriatal regions and their relation to heightened emotional-motivational pain processing.
A potential benefit of the study will be an increase in our knowledge on mechanisms of the development and maintenance of chronic pain in humans with a focus on emotional-motivational processes, deemed to be of very high relevance in this context. Importantly, by implementing and testing a novel conceptual framework, the results will be relevant not only to pain research but also to a broader neuroscientific community, because the expected results also relate to affective and motivational processes in other diseases (e.g. depression, anxiety, Parkinson's disease). The proposed project offers novel avenues to pain treatment based on pharmacological and psychological mechanisms-based approach instead of being symptoms-oriented as most available pain treatments at the moment.
This study entails more than minimal risks and burdens for participants, because the study incorporates the intake of drugs. However, the study requires only low doses and/or single doses of the drug. In this study, patients with fibromyalgia and healthy participants will receive a single dose of the dopamine agonist bromocriptine (1.25 mg, p.o.) or a placebo in separate testing sessions. Healthy participants will receive in an additional testing session a single dose of the dopamine antagonist amisulpride (400 mg, p.o.). Both drugs have been repeatedly used in research with the same dosages with no or very few side effects. The methods that will be used in the experimental testing sessions are within the range of standard procedures in pain research and experimental psychology and are frequently used in healthy participants and patients. Experimental pain stimulation will be adjusted to individual pain sensitivity, rendering the applied stimulation tolerable. Magnetic resonance imaging will be performed without a contrast medium. Peripheral venous blood sampling will be performed by an expert medical professional. The risk of unauthorized data access or unwanted identification of participants will be minimized by the use of restricted access to data and facilities, lockable cabinets, and password protected computers.
The sample consists of fibromyalgia patients and age- and sex-matched healthy controls. While healthy controls undergo three testing sessions to assess the effects of a dopamine receptor antagonist and agonist in comparison to placebo, fibromyalgia patients perform only two testing sessions assessing only the effects of a dopamine agonist in comparison to a placebo, because for these patients the presence of a hypodopaminergic state is assumed. Thus, each session comprises the intake of a single dose of a drug or placebo and MRI scanning. Healthy controls will take in amisulpride (dopamine receptor antagonist), bromocriptine (dopamine receptor agonist), and placebo and fibromyalgia patients bromocriptine and placebo in a counterbalanced order. At the beginning of the first session, written consent will be obtained from the participants after explaining them the purpose and the course of the experiment. After intake of the capsules containing drug/placebo, there will be a waiting period to reach the peak plasma concentration of the drugs during MRI scanning. During this waiting period, participants will fill out some questionnaires. Before the MRI scanning, in each testing session, pain assessments will be performed, which includes assessment of participants individual heat pain threshold and tolerance. This will be followed by taking a blood sample to determine prolactin levels, pro-inflammatory cytokines and anti-inflammatory cytokines and neurofilaments, after which participants will be positioned inside the MRI scanner. During MRI scanning, participants will perform a behavioral discrimination task and an avoidance task to assess sensory-discriminative and emotional-motivational pain components. After completion of these tasks, resting state fMRI will be performed followed by a structural MRI acquisition for obtaining anatomical images. The duration for each testing session is 3-3.5h.
Sample sizes are based on a priori sample size calculations using G\*Power 3.1 with a desired medium effect size f= 0.25, alpha = 0.05, beta= 0.95, repeated measures ANOVA within-between subject designs, and an attrition rate of 10%. Outcome variables will be analyzed in separate mixed model analyses for ANOVA designs with appropriate within- and between-subject factors. Associations of primary endpoints with questionnaire scores (secondary outcomes) will be analyzed using Pearson- or Spearman correlation coefficients, where appropriate. Significance levels will be set to 5%, adjusted with false discovery rate for multiple testing. Effect sizes will be calculated in terms of generalized eta-squared (ηG2) and Cohen's d. Images from fMRI analysis of each participant will undergo standard preprocessing (including high-pass filtering, motion correction, spatial smoothing) and will be entered into a voxel-wise analysis using a general linear model to estimate the effects of pharmacological interventions on pain-related brain activity related to emotional-motivational and sensory-discriminative pain responses. For all brain analyses, a voxel-threshold of p\<0.01 and a cluster threshold for spatial extent of p\<0.05 will be employed.
Within this study, pharmacological interventions, psychophysical methods, and magnetic resonance imaging will be utilized to investigate the neurobiological mechanisms involved in a negative hedonic shift in chronic pain. Pharmacological interventions (amisulpride and bromocriptine) will only cause a transient manipulation of dopaminergic system in both healthy controls and fibromyalgia patients. The pharmacological interventions proposed in the current study does not have a clinical intervention value, instead they are only used for the purpose of investigating psychobiological mechanisms underlying chronic pain. Psychophysical methods will allow the investigators to dissociate the emotional-motivational component of pain from its sensory discriminant component. Magnetic resonance imaging will allow the investigators to investigate brain responses and neuroinflammation in relation to chronic pain. Based on these methods, the investigators will get insights on the role of dopamine and fronto-striatal BOLD response and connectivity in regulating the emotional component of pain in chronic pain. The usage of the pharmacological interventions in this study hold more than minimal risks for the participants, but according to previous research studies, in which the same dosage of these pharmacologic drugs were used, only minimal side-effects have been observed (see above "Risk/Benefit Assessment"). Psychophysical methods and pharmacological interventions based on experimental psychology and pain research will be used in this study. These methods have been shown to be successful in investigating the different aspects of pain perception and modulation of pain perception. The methods used are in the standard range of methods from human pain research and experimental psychology. The expected results will form the basis for the development of novel mechanism-based pain therapies.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 48
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Fibromyalgia patients Bromocriptine Mesylate Capsules In this arm, fibromyalgia patients will receive placebo or a dopamine receptor agonist to investigate the effects of normalizing dopamine transiently on fronto-striatal connectivity and BOLD response in relation to emotional-motivational pain processing. Healthy controls Amisulpride 400 MG In this arm, healthy controls will be administered placebo or a dopamine receptor agonist or a dopamine receptor antagonist on separate days to investigate the role of dopamine and fronto-striatal functional connectivity and BOLD response in relation to emotional-motivational pain processing. Fibromyalgia patients Placebo In this arm, fibromyalgia patients will receive placebo or a dopamine receptor agonist to investigate the effects of normalizing dopamine transiently on fronto-striatal connectivity and BOLD response in relation to emotional-motivational pain processing. Healthy controls Placebo In this arm, healthy controls will be administered placebo or a dopamine receptor agonist or a dopamine receptor antagonist on separate days to investigate the role of dopamine and fronto-striatal functional connectivity and BOLD response in relation to emotional-motivational pain processing. Healthy controls Bromocriptine Mesylate Capsules In this arm, healthy controls will be administered placebo or a dopamine receptor agonist or a dopamine receptor antagonist on separate days to investigate the role of dopamine and fronto-striatal functional connectivity and BOLD response in relation to emotional-motivational pain processing.
- Primary Outcome Measures
Name Time Method Blood oxygen level dependent (BOLD) responses approx. 90 minutes blood oxygen level dependent (BOLD) signal variance (%) from the baseline
Sensory pain responses approx. 20 minutes correct responses in the task assessing sensory-discriminative pain responses
Emotional pain responses approx. 20 minutes correct responses in task assessing emotional-motivational pain responses
- Secondary Outcome Measures
Name Time Method reaction time (RT) approx. 15 minutes reaction times during behavioral tasks
pain threshold 5 minutes Individual pain threshold assessed with experimental heat pain (°C). Participants press the space bar when the temperature start to be painful.
Beck Depression Inventory (BDI) during the procedure, at day 1 The Beck Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression (Beck, et al., 1961). The BDI has been developed in different forms, including several computerized forms, a card form (May, Urquhart, Tarran, 1969, cited in Groth-Marnat, 1990), the 13-item short form and the more recent BDI-II by Beck, Steer \& Brown, 1996. (See Steer, Rissmiller \& Beck , 2000 for information on the clinical utility of the BDI-II.) The BDI takes approximately 10 minutes to complete, although clients require a fifth - sixth grade reading level to adequately understand the questions (Groth-Marnat, 1990)
Self-Compassion Scale, Short Form (SCS-SF) during the procedure, at day 1 Self-compassion entails being kind and understanding toward oneself in instances of pain or failure rather than being harshly self-critical; perceiving one's experiences as part of the larger human experience rather than seeing them as isolating; and holding painful thoughts and feelings in mindful awareness rather than over-identifying with them. Evidence for the validity and reliability of the scale is presented in a series of studies. Results indicate that self-compassion is significantly correlated with positive mental health outcomes such as less depression and anxiety and greater life satisfaction. Evidence is also provided for the discriminant validity of the scale, including with regard to self-esteem measures.
pain tolerance 5 minutes Individual pain tolerance assessed with experimental heat pain. (°C). Participants press the space bar when they cannot tolerate a higher temperature.
perceived pain unpleasantness approx. 33 minutes Individual perceived pain unpleasantness assessed with experimental heat pain. Participants rate the stimuli by moving a cursor with the arrows keys on a scale from -100 (extremely unpleasant) to +100 (extremely pleasant). The middle of the scale has a mark at 0 (neutral).
The Resilience Scale (RS-25) during the procedure, at day 1 The Resilience Scale (RS25) is an instrument developed by Wagnild and Young (1993) to assess resilience levels in adults. There's seven numbers per items on the scale, ranging from "1" (Strongly Disagree) on the left to "7" (Strongly Agree) on the right. A higher score means a better resilience.
Neurofilament Analysis during the procedure, at day 1 Concentration of Neurofilament will be than determined with a new-generation automatised immunoassay method, the simple plex ELISA.
Pro-inflammatory and anti-inflammatory cytokines during the procedure, at day 1 Concentration of cytokines will be identified in collected blood samples using U-PLEX MSD multiplexing panel
The Gratitude Questionnaire-Six Item Form (GQ-6) during the procedure, at day 1 The Gratitude Questionnaire-Six-Item Form (GQ-6) is a six-item self-report questionnaire designed to assess individual differences in the proneness to experience gratitude in daily life.
Snaith Hamilton Pleasure Scale (SHAPS) during the procedure, at day 1 The SHAPS is a 14-item scale that measures anhedonia, the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, sensory experience, and interest/pastimes. Participants tick one of the boxes to indicate how much they agree or disagree with each statement from 1 (strongly disagree) to 4 (strongly agree). Higher score means a better ability to experience pleasure.
perceived pain intensity approx. 33 minutes Individual perceived pain intensity assessed with experimental heat pain. Participants rate the stimuli by moving a cursor with the arrows keys on a scale from 0 (no sensation) to 200 (highest temperature tolerable). The middle of the scale has a mark at 100 (pain threshold).
Pain Catastrophizing Scale (PCS) during the procedure, at day 1 The PCS was developed in 1995 at the University Centre for Research on Pain and Disability in order to facilitate research on the mechanisms by which catastrophizing impacts on pain experience. Catastrophizing is currently defined as: an exaggerated negative mental set brought to bear during actual or anticipated painful experience.
Life Orientation Test - Revised (LOT-R) during the procedure, at day 1 A 10-item measure of optimism versus pessimism.
State-Trait Anxiety Inventory (STAI form Y-1) The questionnaire will be filled thrice at three different timepoints in each testing session The State-Trait Anxiety Inventory (STAI) is a commonly used measure of trait and state anxiety (Spielberger, Gorsuch, Lushene, Vagg, \& Jacobs, 1983). It can be used in clinical settings to diagnose anxiety and to distinguish it from depressive syndromes. It also is often used in research as an indicator of caregiver distress (e.g., Greene et al., 2017, Ugalde et al., 2014).
Urgency, Premeditation (lack of), Perseverance (lack of), Sensation Seeking, Positive Urgency, Impulsive Behavior Scale (UPPS-P, Short version) during the procedure, at day 1 The UPPS-P model of impulsivity proposes that impulsivity as a multi-faceted and multi-dimensional construct, comprising five impulsive personality traits.
Emotion Regulation Questionnaire during the procedure, at day 1 It is a 10-item scale which measures the tendency of the participant to regulate their emotions.
Prolactin and Estradiol during the procedure, at day 1, day 2 and day 3 Concentration of prolactin and estradiol will be identified in collected blood samples
Chronic Pain Acceptance Questionnaire - Revised (CPAQ-R) during the procedure, at day 1 The 20-item CPAQ-revised has been designed to measure acceptance of pain. The acceptance of chronic pain is thought to reduce unsuccessful attempts to avoid or control pain and thus focus on engaging in valued activities and pursuing meaningful goals.
Structured Clinical Interview for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) (SCID-5) during the procedure, at day 1 The Structured Clinical Interview for DSM-5 (SCID-5) is a semistructured interview guide for making the major DSM-5 diagnoses. It is administered by a clinician or trained mental health professional who is familiar with the DSM-5 classification and diagnostic criteria. The interview subjects may be either psychiatric or general medical patients-or individuals who do not identify themselves as patients, such as participants in a community survey of mental illness or family members of psychiatric patients.
The Need Inventory of Sensation Seeking (NISS) during the procedure, at day 1 The Need Inventory of Sensation Seeking (NISS) by Roth and Hammelstein (2012) conceptualizes sensation seeking as a motivational trait, a need for stimulation that can provoke different behaviors.
West Haven-Yale multidimensional pain inventory - Part A during the procedure at day 1 Components of chronic pain experience are assessed using this questionnaire
Fear of Avoidance Beliefs (FABQ) during the procedure, at day 1 FABQ focuses on how a patient's fear avoidance beliefs about physical activity and work may affect and contribute to their low back pain and resulting disability
Fear of Pain Questionnaire (FPQ-III) during the procedure, at day 1 FPQ-III is one questionnaire which is a widely used to assess the fear of pain (FOP) in clinical and non clinical samples. It is one self-report instrument that was developed specifically to assess fear of different stimuli usually causing pain.
Big Five Personality Traits Questionnaire during the procedure, at day 1 It measures the big five dimensions of personality
Positive and Negative Affect Schedule (PANAS) during the procedure, at day 1, day 2 and day 3 Mood will be assessed using PANAS
Trial Locations
- Locations (1)
Balgrist Campus
🇨🇭Zürich, Switzerland