Immunologic Response to Negative Cognition in Persons With Chronic Pain
Condition: Chronic Pain
MeSH terms: Chronic Pain
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Principal Investigator/Program Director (Last, First, Middle): Darnall, Beth APS Future
      Leaders in Pain Small Research Grants Application Page 5 Continuation Format Page

      Summary: Chronic pain is stressful, both physically and psychologically. Stressful
      experiences induce autonomic nervous system arousal, which reliably leads to inflammation and
      immune suppression. Inflammation then exacerbates existing pain and may be a key factor in
      both the genesis and maintenance of pain. Stress-induced immune effects are detected two
      hours (2 hrs) post-stressor, suggesting only a few stressful experiences per day may be
      sufficient to sustain elevated pain levels1. Cognition has emerged as a potential mediating
      factor in the relationship between pain and stress. Mentally recreating an emotionally
      stressful event induces de novo physiological stress1. In other words, thinking about an
      emotionally charged event down-regulates autonomic stress responses and subsequent immune
      effects. Therefore, exploring cognition as a mediating factor between stress, pain, and
      inflammation will inform our understanding of pain pathways, as well as improve treatment for
      pain.

      Study Rationale: The acute stress response induces immunosuppression; however, this
      relationship has been studied in arbitrary models only (shock avoidance, job interview). This
      study employs the novel approach of examining stress and immune responses to a personally
      relevant stressor (pain); prior studies used arbitrary models only (shock avoidance, job
      interview). Pain offers a highly salient and personal context well-suited for investigation
      of negative cognitive perseveration. Pain is acutely sensitive to exacerbation via
      inflammation, and thus the relevance of examining immune effects of rumination on future
      negative expectations ("expecting the worst") is underscored.

      Goal: To test the biological consequences of negative expectations, achieved via an active
      10-minute negative cognitive perseveration on a personally relevant stressor: future
      worsening of one's chronic pain condition. Biological stress response will be measured via
      heart rate (HR), blood pressure (BP) and serum cortisol. Impact of negative cognition on
      inflammation will be measured using interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor
      necrosis factor-alpha (TNF-α) as biomarkers of immune function, controlling for depression
      and pain catastrophizing. This study aims to inform the understanding of pain mechanisms.

      Aim 1: Determine the magnitude of an autonomic stress response to an induction of negative
      cognition.

      Aim 2: Determine immune effects of the experiment-induced stress response.

      Aim 3: Establish whether a pre-existing tendency to catastrophize mediates the relationship
      between experiment-induced negative perseveration and immune effects.

      Aim 4: Establish whether stress-related increases in IL-6 remain elevated post 2 hrs.
    

Detailed description: 
      Methods: This prospective study examines the magnitude of biological stress and subsequent
      immunologic changes in response to negative cognitive perseveration. Five physiological
      measurement time points occur over the course of the 3 hour experiment.

      Demographics and health characteristics of interest: gender, marital status, smoking status,
      education level, race, height, weight, body mass index, medical comorbidity, psychological
      comorbidity, medications (for inflammation, pain, or psychiatric conditions).

      Inclusionary Criteria

        -  >18 years of age; <65 years of age

        -  Non-inflammatory musculoskeletal patients presenting for evaluation at Oregon Health &
           Science University (OHSU) Comprehensive Pain Center (CPC)

      Exclusionary Criteria

        -  Active or recent virus/infection

        -  Thought disorder, Suicidality,

        -  Substance Abuse

        -  Active corticosteroid regimen

        -  Pregnancy

        -  Limited venous access

        -  Former intravenous drug user

      Enrollment: All persons presenting for evaluation at the CPC who meet study criteria will be
      offered the option to participate in the study. Approximately 60 new pain patients are
      evaluated by psychology monthly and we expect to obtain our goal of 40 participants within 6
      months. Informed consent will be obtained in compliance with OHSU Institutional Review Board
      protocol. Subjects will receive $100 gift certificate compensation, even if they fail to
      complete the study. We anticipate a low completion failure rate as the study is completed in
      one 3-hour time block. Study times will be standardized to account for circadian effects.
      Participants will be told to arrive having eaten a light breakfast with minimal caffeine
      consumption (e.g., less than 2 cups of coffee). They will be given a subject number and their
      psychiatric diagnoses will be blinded to prevent bias. The study involves gathering 5 serum
      samples and thus participants will be catheterized by nursing staff to minimize physiological
      stress.

      Principal Investigator/Program Director (Last, First, Middle): Darnall, Beth APS Future
      Leaders in Pain Small Research Grants Application Page 7 Continuation Format Page

      Study site: The study will be conducted at the NIH-funded General Clinical Research Center
      (GCRC). The GCRC provides state of the art resources including research space, specialized
      research nurses to perform blood draws and gather biodata, biostatisticians, and
      sophisticated laboratories to perform serum biomarker analysis. OHSU's GCRC is Oregon's
      premier multidisciplinary patient-oriented research facility and is housed in the same
      building as the CPC, thus minimizing travel burden on participants.

      Active Stress Induction: Negative Cognitive Perseveration On their experiment day,
      participants will interface with a licensed clinical psychologist who did not perform their
      clinical interview and who is blinded to their diagnoses. The psychologist will instruct the
      participant talk for 10 minutes about the worst aspects of their pain, to discuss their loss
      of control over their situation, the negative impact pain has had on their life and others.
      They will be guided to imagine that their situation will progressively worsen, and to focus
      on how badly they will feel as a result. Two measures of induction efficacy will be given:
      subjective verbal rating (0-10) and objective rating by attending psychologist (0-10). The
      intervention ends at 10 minutes and the remainder of the study involves biodata measurement.

      Study ends at 2.5 hrs post induction following the final blood draw. The psychologist will
      debrief subjects and will assess their affective state. Their subjective units of distress
      will be checked. Persons who are in a continued negative cognitive state will receive 30
      minutes of Cognitive Behavioral Therapy (CBT) by the on-site psychologist. Care will be taken
      not to allow participants to leave the study site in distress. Participants will receive
      follow up psychology care at the CPC as indicated in their treatment plan.
    

Intervention name(s): In-vivo pain catastrophizing induction
Intervention type(s): Behavioral
Intervention description(s): All participants underwent a 10-minute in-vivo pain castastrophizing induction.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Primary purpose: Other
Keywords: Chronic pain; Interleukin-6; pain catastrophizing; cytokines; cortisol