Psychobiological Mechanisms Underlying Chronic Pain

NCT04674670 | Completed

• 1 other identifier: PR00P1_179697/1_3_4
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

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.

Conditions

Fibromyalgia; Pain, Chronic; Chronic Pain, Widespread

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

Outcome Measures

Primary Outcomes (3)

• Blood oxygen level dependent (BOLD) responses

  blood oxygen level dependent (BOLD) signal variance (%) from the baseline

  approx. 90 minutes

• Sensory pain responses

  correct responses in the task assessing sensory-discriminative pain responses

  approx. 20 minutes

• Emotional pain responses

  correct responses in task assessing emotional-motivational pain responses

  approx. 20 minutes

Secondary Outcomes (26)

• reaction time (RT)

  approx. 15 minutes

• pain threshold

  5 minutes

• pain tolerance

  5 minutes

• perceived pain intensity

  approx. 33 minutes

• perceived pain unpleasantness

  approx. 33 minutes

Study Arms (2)

Healthy controls

EXPERIMENTAL

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.

Drug: Bromocriptine Mesylate Capsules; Drug: Amisulpride 400 MG; Drug: Placebo

Fibromyalgia patients

EXPERIMENTAL

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.

Drug: Bromocriptine Mesylate Capsules; Drug: Placebo

Interventions

Bromocriptine Mesylate Capsules DRUG

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.

Fibromyalgia patients; Healthy controls

Amisulpride 400 MG DRUG

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

Placebo DRUG

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.

Also known as: Placebo for substudy 2

Fibromyalgia patients; Healthy controls

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• susanne becker: lead
• SNSF: collaborator

Study Sites (1)

Balgrist Campus

Zurich, 8008, Switzerland

Location

MeSH Terms

Conditions

Fibromyalgia; Chronic Pain; Acute Pain

Interventions

Bromocriptine; Amisulpride

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ergotamines; Ergot Alkaloids; Alkaloids; Heterocyclic Compounds; Ergolines; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Susanne Becker, PD Dr.

  Balgrist Universitätsklinik

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blinded randomized placebo-controlled between-within-subject cross-over design with repeated measures; Participants and experimenter will be blinded through out the complete data collection. In addition, participants are not fully instructed about the purpose of the specific tests during the test session, but will be debriefed after final testing session.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Research Group

Model Details: 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.

Study Record Dates

• First Submitted: December 3, 2020
• First Posted: December 19, 2020
• Study Start: November 1, 2021
• Primary Completion: July 31, 2023
• Study Completion: July 31, 2023
• Last Updated: September 7, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)