Pain Catastrophizing as a Cause for Systemic Inflammation
Condition: Musculoskeletal Pain
MeSH terms: Musculoskeletal Pain; Inflammation
Study type: Interventional
Phase: Phase 1

Summary: 
      Research shows that the immune system is involved in chronic pain. The immune system is
      involved in the process of inflammation. The investigators are still learning about the
      factors that cause inflammation, but know it can be measured in the blood. The purpose of
      this study is to understand how negative thoughts affect the immune system in women with
      chronic pain.

      A sub-study asks subjects to store a blood sample for future research by the PI aimed at
      identifying genetic markers in women with chronic pain.
    

Detailed description: 
      A main goal of the study is to better understand pain mechanics. Research has linked
      pro-inflammatory cytokines to the development and progression of pain. Research has also
      linked female gender with increases in pro-inflammatory cytokines (relative to males)
      following psychological stress. Therefore, we hypothesize that women in the study who
      evidence significantly increased pro-inflammatory cytokines following pain catastrophizing
      may be at risk for the progression of their pain condition.

      The sample will be 60 women having chronic musculoskeletal pain (we will enroll up to 75
      persons to account for attrition and screen failures but require the usable data of only 60
      women). Based on enrollment rates for our previous study, and given our expanded catchment
      area, we expect to enroll 60 persons within approximately 14 months and to complete the
      experimental phase of the study within approximately 17 months. The follow-up phase of the
      study will continue, for as long as participants agree to be followed for up to 10 years.

      The study design is a randomized, controlled experiment. Participants are consented and
      enrolled under the impression that they will undergo one stress experiment day (lasting about
      5.5 hours). However, on their study day we will randomize subjects to either be in the
      control group or the catastrophizing (stress) group.

      Screening Visit: The purpose of this visit is to determine eligibility and obtain informed
      consent. Inclusion and exclusion criteria will be assessed through medical record review, a
      screening interview, and a hormonal bloodspot kit. A questionnaire will also be given to
      determine level of depressive symptoms and to assess for suicidality. The hormonal bloodspot
      kit involves a finger prick and obtaining about 5-6 drops of blood. If lab analysis of this
      kit determines abnormal hormonal levels, persons will be excluded from further participation
      in the study. Participants will be given a saliva kit to gather 4 saliva samples at home over
      the course of one day. Participants will store these saliva samples in their refrigerator.
      They will either bring in the kit at the time of their study visit or mail the kit in a
      prepaid box given to them (the hormones in the saliva are shelf stable for up to 3 weeks; we
      will ask participants to refrigerate the samples if they are not immediately mailing them or
      bringing them to the study site. In this way we will best ensure that samples will be
      preserved and usable). All participants enrolled in the study will be under the impression
      that they will be participating in a catastrophizing experiment during their study day.
      However, only half of the participants will actually experience the 10-minute stress
      experiment on experiment day. We have included this minor form of deceit in the protocol so
      we can control for the anticipatory stress of expecting to experience a negative emotional
      experiment. We highlight here that the mild deception will occur for only half the sample
      (those going into the control group) and it represents a decrease in risk for these persons.

      Study Visit: This study visit is scheduled to occur during the follicular phase of the
      menstrual cycle (this phase follows the menstrual period and is easy to predict in our sample
      of normally menstruating women by using a calendar). If difficulty is encountered in
      predicting the date of the follicular phase, participants will call the PI or study
      coordinator when their menstrual period begins to schedule their study date (approximately
      5-6 days from onset on menses). All participants arrive in a fasting state, during their
      follicular phase to control for sex-steroid influences on immunity. 3ml of blood will be
      drawn for hormone levels. The hormone level will not be analyzed at this time, but saved
      until the end of the study for analysis, if needed. A complete cardiometabolic panel will be
      measured via bloodspot. If the subject agrees to take part in the sub study, we will take an
      additional 10mL of blood for an extra bloodspot card that we will store for future
      pain/genomic research. Pain ratings will be assessed, and questionnaires will be completed.
      Standardized meals (with no caffeine) will be served to participants (breakfast, lunch,
      snacks). An OCTRI research nurse will place an intravenous catheter into the arm of
      participant's choosing. A Holter heart monitor will be placed on participants by nursing.
      This is a portable device that measures heart beat. Placement of the leads around the heart
      involves cleaning the skin. The monitor will remain affixed for the duration of the study
      visit. At this point participants will be randomized to either be in the control group or in
      the catastrophizing group using a random number generator. After they are randomized into one
      of the two groups, the deception will be revealed to the control group, and its rationale
      explained. Those randomized to the stress group will be informed of the deception, and the
      rationale for having used it, at the conclusion of the study visit .

      Those in the control group will have serum measurements taken at the time points listed in
      the study activities table below. They will occupy themselves for the next 4.5 hours with
      activity options to keep them from sleeping during the study visit, such as reading
      magazines, crossword puzzles, or games. We will have these on hand, or they can bring them to
      the visit. At each time point, salivary cortisol, heart rate, blood pressure, and pain
      ratings will be assessed. At the end of the final blood draw, the IV catheter is removed and
      the first study visit is complete.

      Those persons randomized to the catastrophizing group will undergo a 10min pain
      catastrophizing induction following the 25 min post- IV catheterization rest period (we are
      also calling this the stress experiment). The PI will guide participants to focus on their
      pain, to imagine it worsening in the near future, and to describe how their worsening pain
      will affect life domains most important to them. The induction is standardized in the
      following ways: 1) duration of induction (10 minutes); 2) imaginal focus on pain worsening in
      the near future; 3) participants are guided to describe the anticipated negative consequences
      of their pain worsening; 4) participants will be guided to describe the ways in which they
      feel helpless while imagining the scenario. Items 2-4 are designed to tap the 3 components of
      pain catastrophizing (rumination, magnification of pain, helplessness).

      Pain ratings and stress response will be measured via heart rate and blood pressure and
      salivary cortisol according to the study activities table below. No bloodspot kits will be
      collected during this visit. This study visit ends after the 270min post-induction blood
      draw. The PI will debrief subjects and assess their affective state. Free counseling will be
      offered before the subject leaves the study visit (only one person in the previous study
      opted for the post-study counseling). If anyone in the stress group would like a counseling
      referral the PI will provide local options to them. All participants receive a next-day
      telephone call to assess for mood state and adverse events.

      Long-term Follow-Up: We have included a separate consent form to allow us to follow subjects
      over time. A main goal of the study is to better understand pain mechanics. Research has
      linked pro-inflammatory cytokines to the development and progression of pain. Research has
      also linked female gender with increases in pro-inflammatory cytokines (relative to males)
      following psychological stress. Therefore, we hypothesize that women in the study who
      evidence significantly increased pro-inflammatory cytokines following pain catastrophizing
      may be at risk for the progression of their pain condition. We expect that if we follow our
      sample over time, we will see a trend that will serve as preliminary data to allow us to
      investigate this further. While the catastrophizing experiment will provide us with
      meaningful data, this longitudinal sub study will allow us to define the clinical and
      functional relevance of our findings. For those who consent to this related study, subjects
      will be contacted every 6 months for up to 10 years and asked several questions about their
      pain, mood, function, and stress levels. They will also be asked to complete 4 questionnaires
      including: the Oswestry Disability Index, The CES-D form, and the Perceived Stress Scale.
      These questionnaires can be read to the subject over the phone or completed on paper. If the
      subject would like to complete them on paper, an address, stamped return envelope will be
      provided. They will also be asked if we can contact them again in 6 months.
    

Intervention name(s): Pain Catastrophizing Induction
Intervention type(s): Behavioral
Intervention description(s): Participants will undergo a psychologist-guided 10-minute induction of negative cognitive focus on the theoretical future worsening of one's pain condition.Biological stress response will be measured via heart rate, blood pressure and serum cortisol.
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Diagnostic
Keywords: Pain; Systemic Inflammation; Pain Catastrophizing