Psychobiological Mechanisms Underlying Chronic Pain
Condition: Fibromyalgia; Pain, Chronic; Chronic Pain, Widespread
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes; Chronic Pain
Study type: Interventional

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.
    

Intervention name(s): Bromocriptine Mesylate Capsules; Amisulpride 400 MG; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Healthy controls and fibromyalgia patients will be administered a single dose of bromocriptine (1.25mg, p.o.) to investigate the effect of transiently increasing the availability of dopamine on fronto-striatal functional connectivity and BOLD response in relation to emotional-motivational pain processing.; Healthy controls will be administered a single dose of amisulpride (400mg, p.o.) to investigate the effect of transiently decreasing the availability of dopamine on fronto-striatal functional connectivity and BOLD response in relation to emotional-motivational pain processing.; Healthy controls and fibromyalgia patients will be administered a placebo as for comparison with the effects of bromocriptine (healthy controls and patients) and amisulpride (healthy controls only) on fronto-striatal functional connectivity and BOLD response in relation to emotional-motivational pain processing.
Other intervention name(s): Placebo for substudy 2
Intervention MeSH terms: Bromocriptine; Amisulpride
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The drugs that will be used in this study will not be utilised as therapeutic clinical interventions, but as modulators of endogenous process and to assess psychobiological mechanisms in pain processing. Healthy controls will be administered with placebo or a dopamine agonist (bromocriptine) or a dopamine antagonist (amisulpride) on separate days to investigate the role of dopamine and fronto-striatal functional connectivity and BOLD response in relation to emotional-motivational component of pain. Fibromyalgia patients receive only placebo or a dopamine agonist to see the effects of normalization of dopamine on fronto-striatal connectivity and BOLD response, because a lowered dopamine level is assumed to decrease the emotional-motivational component of pain.
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Fibromyalgia; acute pain; chronic pain; Widespread Pain; hedonic shift; Dopamine; Magnetic Resonance Imaging; Functional connectivity; emotional-motivational components of pain; sensory-discriminative components of pain