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Psychobiological Mechanisms Underlying Chronic Pain

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ClinicalTrials.gov Identifier: NCT04674670
Recruitment Status : Not yet recruiting
First Posted : December 19, 2020
Last Update Posted : December 19, 2020
Sponsor:
Collaborator:
SNSF
Information provided by (Responsible Party):
susanne becker, Balgrist University Hospital

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 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 causal role of neuroinflammation (substudy 1) and the role of dopamine (substudy 2) in functional connectivity of fronto-striatal brain networks and their relation to heightened emotional-motivational pain processing.

Condition or disease Intervention/treatment Phase
Fibromyalgia Pain, Chronic Chronic Pain, Widespread Drug: Low dose naltrexone Drug: Placebo Drug: Bromocriptine Mesylate Capsules Drug: Amisulpride 400 MG Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: The drugs that will be used in both substudies will not be utilized as therapeutic clinical interventions, but as modulators of endogenous process and to assess psychobiological mechanisms in pain processing. Substudy 1 incorporates a 12-weeks a pharmacological intervention (low-dose naltrexone or placebo) in patients with fibromyalgia. Two MRI scanning sessions will be conducted (pre- and post-treatment). In substudy 2, healthy controls will be administered 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 in relation to emotional-motivational component of pain. Fibromyalgia patients in substudy 2 will receive only placebo or a dopamine agonist to see the effects of normalization of dopamine on fronto-striatal connectivity, because a lowered dopamine level is assumed to decrease the emotional-motivational component of pain.
Masking: Double (Participant, Investigator)
Masking Description:

Substudy 1: Double-blind randomized placebo-controlled between-within-subject design with repeated measures; Participants and experimenter are blinded to whether participants receive the drug or the placebo. In addition, participants are not fully instructed about the purpose of the specific tests during the test session, but will be debriefed after testing.

Substudy 2: Double-blind randomized placebo-controlled between-within-subject cross-over design with repeated measures; Participants and experimenter are blinded to when participants receive each drug and the placebo. In addition, participants are not fully instructed about the purpose of the specific tests during the test session, but will be debriefed after testing.

Primary Purpose: Basic Science
Official Title: The Role of Microglial Activation and Dopamine in Fronto-striatal Connectivity in Emotional-motivational Pain Processing in Patients With Chronic Pain
Estimated Study Start Date : January 2021
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Naltrexone

Arm Intervention/treatment
Active Comparator: Substudy 1: Fibromyalgia patients, active comparator
Substudy 1 incorporates a 12-weeks a pharmacological intervention (drug or placebo) in patients with fibromyalgia and two MRI testing sessions pre- and post-treatment. Low-dose naltrexone (LDN) will be administered as the active comparator in substudy 1 to down-regulate microglial activation.
Drug: Low dose naltrexone
Low dose naltrexone will not be utilized here as therapeutic clinical interventions, but to assess psychobiological mechanisms in pain processing. Participants will receive low dose naltrexone with 4.5 mg p.o. daily over a period of 12 weeks.
Other Name: Naltrexone hydrochloride

Placebo Comparator: Substudy 1: Placebo comparator for Fibromyalgia patients
Substudy 1 incorporates a 12-weeks a pharmacological intervention (drug or placebo) in patients with fibromyalgia and two MRI testing sessions pre- and post-treatment. In this arm, a placebo will be administered for comparison with the low dose naltrexone as the active comparator.
Drug: Placebo
Placebo will be give daily (p.o.) over a period of 12 weeks.
Other Name: Placebo for substudy 1

Experimental: Substudy 2: Healthy controls
In this arm of substudy 2, 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 in relation to emotional-motivational pain processing.
Drug: Bromocriptine Mesylate Capsules
In substudy 2, 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 in relation to emotional-motivational pain processing.

Drug: Amisulpride 400 MG
In substudy 2, 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 in relation to emotional-motivational pain processing.

Drug: Placebo
In substudy 2, 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 in relation to emotional-motivational pain processing.
Other Name: Placebo for substudy 2

Experimental: Substudy 2: Fibromyalgia patients
In this arm of substudy 2, fibromyalgia patients will receive placebo or a dopamine receptor agonist to investigate the effects of normalizing dopamine transiently on fronto-striatal connectivity and emotional-motivational pain processing.
Drug: Bromocriptine Mesylate Capsules
In substudy 2, 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 in relation to emotional-motivational pain processing.

Drug: Placebo
In substudy 2, 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 in relation to emotional-motivational pain processing.
Other Name: Placebo for substudy 2




Primary Outcome Measures :
  1. Brain metabolites [ Time Frame: Only in substudy 1: approx. 30 minutes ]
    Concentration of myo-inositol and choline relative to peak height of creatine as indicators of glia activation

  2. Blood oxygen level dependent (BOLD) responses [ Time Frame: approx. 45 minutes ]
    blood oxygen level dependent (BOLD) signal variance (%) from the baseline

  3. Sensory pain responses [ Time Frame: approx. 20 minutes ]
    correct responses in the task assessing sensory-discriminative pain responses

  4. Emotional pain responses [ Time Frame: approx. 20 minutes ]
    correct responses in task assessing emotional-motivational pain responses


Secondary Outcome Measures :
  1. reaction time (RT) [ Time Frame: approx. 15 minutes ]
    reaction times during behavioral tasks

  2. pain threshold [ Time Frame: 5 minutes ]
    Individual pain threshold assessed with experimental heat pain (°C). Participants press the space bar when the temperature start to be painful.

  3. pain tolerance [ Time Frame: 5 minutes ]
    Individual pain tolerance assessed with experimental heat pain. (°C). Participants press the space bar when they cannot tolerate a higher temperature.

  4. perceived pain intensity [ Time Frame: 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).

  5. perceived pain unpleasantness [ Time Frame: 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).

  6. Pain Catastrophizing Scale (PCS) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  7. Beck Depression Inventory (BDI) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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)

  8. Chronic Pain Acceptance Questionnaire - Revised (CPAQ-R) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  9. The Gratitude Questionnaire-Six Item Form (GQ-6) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  10. Life Orientation Test - Revised (LOT-R) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    A 10-item measure of optimism versus pessimism.

  11. Freiburg Mindfulness Inventory (FMI) (short form) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    Freiburg Mindfulness Inventory(14-items) to measure trait mindfulness

  12. State-Trait Anxiety Inventory (STAI form Y-1) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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).

  13. Self-Compassion Scale, Short Form (SCS-SF) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  14. The Resilience Scale (RS-25) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  15. Snaith Hamilton Pleasure Scale (SHAPS) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  16. Structured Clinical Interview for DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) (SCID-5) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  17. Fear of Avoidance Beliefs (FABQ) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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

  18. Fear of Pain Questionnaire (FPQ-III) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  19. The Need Inventory of Sensation Seeking (NISS) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    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.

  20. Urgency, Premeditation (lack of), Perseverance (lack of), Sensation Seeking, Positive Urgency, Impulsive Behavior Scale (UPPS-P, Short version) [ Time Frame: during the procedure, at day 1 in each substudy (substudy 1 is 3 days and substudy 4 is 2 days) ]
    The UPPS-P model of impulsivity proposes that impulsivity as a multi-faceted and multi-dimensional construct, comprising five impulsive personality traits.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Substudy 1, for fibromyalgia patients

Inclusion Criteria:

  • Age between 18 to 70 years
  • Chronic widespread pain
  • Symptoms such as fatigue, cognitive dysfunction, and/or depressive symptoms
  • Sufficient knowledge of German or English to follow instructions
  • Ability to give written informed consent

Exclusion criteria:

  • Psychiatric or neurological disorders, except depression and anxiety
  • Substance abuse or consumption of alcohol, illegal drugs, analgesics apart from prescribed routine medication within the last 24 h before testing session
  • Pacemaker or metal parts in the body or any contradiction to MRI
  • Pregnancy and breast-feeding
  • Opioid medication and a medical history indicating any risk/allergies using the opioid antagonist naltrexone
  • Liver or/and kidney problems
  • Autoimmune disease
  • Thyroid hormone disease

Substudy 2, for fibromyalgia patients:

Inclusion criteria:

  • Age between 18 to 70 years
  • Chronic widespread pain
  • Symptoms such as fatigue, cognitive dysfunction, and/or depressive symptoms
  • Sufficient knowledge of German or English to follow instructions
  • Ability to give written informed consent

Exclusion criteria:

  • Psychiatric or neurological disorders, except depression and anxiety
  • Substance abuse or consumption of alcohol, illegal drugs, analgesics apart from prescribed routine medication within the last 24 h before testing session
  • Pacemaker or metal parts in the body or any contradictions to MRI
  • Pregnancy and breast-feeding
  • Medical history indicating any risk/allergies using the amisulpride or bromocriptine or both or other ergotamine. Long QT syndrome, cardiac arrhythmia, intake of drugs causing QT prolongation in the electrocardiogram.
  • Liver or/and kidney problems
  • High blood pressure or cardiovascular or heart disease
  • Stomach ulcers or bleeding
  • Fibrosis
  • Diabetes
  • Cancer patients
  • Intake of drugs lowering potassium levels in the blood
  • Blood pressure problems during pregnancy in the past
  • History of breast cancer in the family first-order relatives
  • Cerebrovascular events in anamnesis
  • Simultaneous intake of potent or moderate Cytochrome P450 inhibitors

For Healthy participants:

Inclusion criteria:

  • Age-matched healthy participants
  • Good overall health status
  • Sufficient knowledge of German or English to follow instructions
  • Ability to give written informed consent

Exclusion criteria:

  • Pain longer than 3 consecutive days and on more than 30 days within the last 12 months
  • Major psychiatric or neurological disorders
  • Pregnancy and breast-feeding
  • Substance abuse or consumption of alcohol, illegal drugs, and analgesic drugs within 24 h before testing session
  • Pacemaker or metal parts in the body or any contradiction to MRI
  • Medical history indicating any risk/allergies using the amisulpride or bromocriptine or both or other ergotamine.
  • Liver or/and kidney problems
  • High blood pressure or cardiovascular or heart disease
  • Stomach ulcers or bleeding
  • Fibrosis
  • Diabetes
  • Low potassium levels in the blood
  • Blood pressure problems during pregnancy in the past
  • History of breast cancer in first-order relatives
  • Cerebrovascular events in anamnesis
  • Simultaneous intake of potent or moderate Cytochrome P450 inhibitors

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04674670


Contacts
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Contact: Susanne Becker, PD Dr. +41445107352 susanne.becker@balgrist.ch

Locations
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Switzerland
Balgrist Campus
Zürich, Switzerland, 8008
Sponsors and Collaborators
susanne becker
SNSF
Investigators
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Principal Investigator: Susanne Becker, PD Dr. Balgrist Universitätsklinik
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Responsible Party: susanne becker, Head of Research Group, Balgrist University Hospital
ClinicalTrials.gov Identifier: NCT04674670    
Other Study ID Numbers: PR00P1_179697/1_3_4
First Posted: December 19, 2020    Key Record Dates
Last Update Posted: December 19, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by susanne becker, Balgrist University Hospital:
Fibromyalgia
acute pain
chronic pain
Widespread Pain
hedonic shift
Dopamine
Neuroinflammation
Magnetic Resonance Imaging
Functional connectivity
emotional-motivational components of pain
sensory-discriminative components of pain
Magnetic Resonance Spectroscopy
Additional relevant MeSH terms:
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Fibromyalgia
Myofascial Pain Syndromes
Chronic Pain
Pain
Neurologic Manifestations
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Neuromuscular Diseases
Nervous System Diseases
Naltrexone
Bromocriptine
Amisulpride
Alcohol Deterrents
Narcotic Antagonists
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Second-Generation
Antidepressive Agents
Antiparkinson Agents
Anti-Dyskinesia Agents