Conditioned pain modulation (CPM) is the behavioral measure of diffuse noxious inhibitory control (DNIC), an endogenous pain inhibitory pathway in which pain inhibits pain. Conditioned pain modulation is less efficient in individuals with chronic pain conditions, and it is a predictor for the development of chronic pain. Continuous stimulation of central/cortical mechanisms through engaging CPM might alter pain processing and improve pain inhibition. Healthy participants will be randomly assigned to one of three groups: High Exposure (HE), Low Exposure (LE), and No Exposure (NE). Pre-and post-intervention pain sensitivity including conditioned pain modulation will be assessed. The study will assess the central pain modulatory mechanisms (measured by CPM) that have differential changes in participants who receive high exposure CPM as an intervention from those who receive low or no exposure. The study will also assess the magnitude and efficiency of CPM contributing additional variance to a regression model predicting pain sensitivity after positive and negative affect, pain anxiety, and depression are considered in the model, establishing measures of central pain processing, like CPM, as unique contributors to pain intensity.

Background:

Pain is a widespread health condition that has a large burden on individuals, families, and society. Of the 39.4 million adults with pain that occurs most days and persists for more than three months, nearly two-thirds deem it "constantly present," and over half define it as "unbearable and excruciating". Pain may be classified as physiological and pathological. Nociceptive and inflammatory pain are physiological states that are protective and adaptive, whereas pathological pain is nonprotective and maladaptive.

The conditioned pain modulation (CPM) paradigm is a dynamic QST measure of a pain inhibitory process that lessens pain sensitivity in response to a remotely applied painful stimulus and is used to assess the ability of the person to endogenously inhibit pain. CPM may be a valuable tool in directing mechanistic-based approaches for treating painful conditions. For example, individuals with painful diabetic neuropathy and poorly functioning CPM have more significant analgesia when given duloxetine, a medication that augments conditioned pain modulation. Additionally, identifying and treating the source of pain is associated with positive changes in CPM. Healthy individuals demonstrate more efficient CPM when compared with people in pain and a systematic review of adults with chronic pain revealed that CPM efficiency improves after a reduction in pain. For example, total hip arthroplasty for treating painful osteoarthritis reduces pain and improves post-operative CPM. Collectively, these studies suggest that the CPM test has the potential to predict risk and treatment outcomes for chronic pain., therefore CPM may be considered an essential treatment moderator and mediator.

Activation of these central mechanisms (endogenous inhibitory systems) has also been proposed as the mechanism underpinning interventions used to treat various pain conditions. For example, evidence suggests that descending pain inhibitory systems (central mechanisms) play a fundamental role in mediating the analgesic effect of manipulation-induced pain modulation. Manual therapy activates afferent neuronal inputs that stimulate the central nervous system to inhibit pain through descending modulation. Like manual therapy, CPM inhibits pain through descending modulation. Continuous stimulation of central mechanisms through CPM should therefore alter pain processing and improve pain inhibition.

However, few studies have used CPM as an intervention, and none answer these research questions: 1) Does repeated exposure to conditioned pain modulation affect pain sensitivity? 2) Is analgesic efficacy of the nervous system predicted by the CPM effect? 3) Does CPM have therapeutic implications?

Understanding pain inhibitory mechanisms through this investigation would add further evidence to understanding the mechanism for chronic pain and might be a potential target for treating chronic pain.

Specific Aims:

Aim 1: To determine the extent to which repeated exposure to CPM protocols modifies pain sensitivity.

Hypothesis 1: CPM efficiency will increase in the high-exposure group compared to the low-exposure or No exposure group.

Aim 2: To determine the extent to which expectations affect the change in CPM efficiency.

Hypothesis 2: Participants with positive pain-related expectations will display a greater magnitude of improvement in CPM efficiency.

Research Plan:

The study in this proposal will be based on psychophysical data and self-reported questionnaires using methods approved by the University of Florida Institutional Review Board. This prospective experimental study involves participants without chronic pain conditions who will undergo baseline assessments, including psychological questionnaires and psychophysical approaches to measuring individual sensitivity and endogenous pain modulation. After an intervention period, participants will be reassessed. All assessments will be performed by an evaluator who will be blind to psychological measure data and group assignment.

Participants:

Seventy participants will be recruited by posted fliers approved by the IRB on the University of Florida campus and the Gainesville Florida community.

Inclusion criteria: a) Not currently seeking treatment for pain past month; b) between 18 - 75 years old.

Exclusion criteria: Participants will not be excluded based on race or gender but will be excluded if they meet any of the following a) non-English speaking; b) systemic medical condition is known to affect sensation (i.e., diabetes); c) regular use of prescription pain medication to manage pain; d) current or history of chronic pain condition; e) currently using blood thinning medication; f) any blood clotting disorder such as hemophilia; g) any contraindication to the application of ice or cold packs, such as uncontrolled hypertension, cold urticaria, cryoglobulinemia, paroxysmal cold hemoglobinuria, and circulatory compromise; h) involved in vigorous physical activities like heavy lifting, digging, aerobics or fast bicycling.

Recruitment and Informed Consent Procedure:

Potential participants interested in the study will respond to posted fliers and contact either the primary Investigator or co-investigator by phone or e-mail. The primary Investigator or co-investigator will read from an IRB-approved phone script or respond through an IRB-approved e-mail script to provide an overview of basic information about the study and answer questions. Participants wishing to participate will be scheduled for the formal consent process with either the Principal Investigator or co-investigator. Informed consent will occur in the Department of Physical Therapy lab space in the Health Science Center's Dental Wing. At that time, the primary Investigator or co-investigator will explain the study procedure, study purpose, benefits/risks of participating, and use of protected health information. The investigators will ensure appropriate time is spent with the participant to answer any questions and ensure he or she understands the procedures and risks associated with the study. If the participant chooses to participate, informed consent will be obtained from the participant as appropriate.

Measures:

Measures will be collected by the primary investigator, co-investigator, and/or research assistant under the direct supervision of the primary or co-investigator.

Questionnaires:

Demographic and Historical Factors:

Study participants will complete a standard intake information form including gender, age, employment status, marital status, educational level, and health history.

Expectation: Individuals will be asked what they expect exposure to the coldpressor task to do the amount of pressure needed to generate pain (see "Intervention" for the coldpressor task).

Quantitative Sensory Testing:

Conditioned Pain Modulation (as an assessment): Participants will receive a testing stimulus of pressure applied to the web space of the dominant foot. Pressure will be applied per ascending intensity until the pain reaches 40 out of 100, then discontinued. Participants are instructed to say "stop" or "pain" so the stimulus can be terminated "when you feel pain equal to 40 out of 100." Participants will then receive a conditioning stimulus contact heat stimulus applied to the thenar of the left hand for 60 s at an intensity of 46.5 ◦C (Matre, 2013). Subjects will be asked to rate the heat pain and unpleasantness during a 60-second trial. Subjects will be instructed that they may remove their hand at any time if the heat is intolerable. After 60 seconds, the contact heat will be completely removed, and the testing stimulus will be re-applied to the web space of the dominant foot. Conditioned pain modulation will be calculated as the average pain ratings of the second testing stimulus series minus the average pain ratings of the first testing stimulus series. Negative numbers indicate efficient pain modulation.

Procedure:

Participants who consent will sign up for individual blocks of testing time (90 minutes) to take part in the experiment. Participants who consent will sign up for individual blocks of testing time (90 minutes) to take part in the experiment. Participants will complete expectation questions before every protocol session. Blood pressure will be assessed with a digital blood pressure monitor before every session. If blood pressure exceeds 140/90 mmHg, the participant will be removed from the study session and notified of the blood pressure reading. Next, a baseline assessment of pain sensitivity will be completed. After testing, participants sit quietly for 15 minutes to allow changes in pain sensitivity to normalize after pre-intervention CPM testing (Lewis et al., 2012). Individuals will be randomized to one of three groups: High Exposure (HE), Low Exposure (LE), No Exposure (NE).

High Exposure: Participants will receive five sessions total: four sessions of the Intervention, questionnaires, quantitative sensory testing, and CPM as an outcome in the first and fifth sessions.

Low Exposure: Participants will receive only two sessions in total: questionnaires, quantitative sensory testing, and CPM as an outcome at both sessions.

No Exposure: This group controls for natural history response, and participants will receive two sessions of questionnaires, and CPM as an outcome, and quantitative sensory testing for one session (last session).

High exposure group will be attending 5 sessions (about once every 72 hours) for two weeks. The other two groups (Low Exposure and No Exposure) come twice (the second visit about 2 weeks later). Visits can last 1 to 1.5 hours.

Intervention:

CPM: Participants will receive a testing stimulus of pressure applied to the web space of the dominant foot. Pressure is applied per ascending intensity until the pain reaches 40 out of 100, then discontinued. Participants will be instructed to say "stop" or "pain" so the stimulus can be terminated "when you feel pain equal to 40 out of 100." This will be repeated twice, and the average will be analyzed (Yarnitsky et al., 2015). Participants will then receive a conditioning stimulus by immersing non-dominant hand into the water cooled by a refrigeration unit (NESLAB RTE 7 Digital One, Thermo Scientific Co., Massachusetts, USA) that circulates water continuously to maintain a constant temperature of six degree Celsius (males) or eight degree Celsius (females) for 60 seconds. Subjects will be asked to rate the cold pain and unpleasantness during the four 60-second trials. Subjects will be instructed that they may remove their hand at any time if the water is intolerable. If this occurs, or if subjects rate the pain higher than 50 (0-100 scale), the bath temperature will be increased for the subsequent trial. If the ratings are less than 20, a small about of ice was added to lower the temperature by up to 4o Celsius. Participants completely removed their hand from the cold pressor for 30 seconds following each of the four 60-second immersions, during which time the testing stimulus will be re-applied per the sequential paradigm to the web space of the foot. Participants complete four 60-second periods of immersion. Conditioned pain modulation will be calculated as the average pain ratings of the second testing stimulus series minus the average pain ratings of the first testing stimulus series. Negative numbers indicate efficient pain modulation.

Immediately following the assigned intervention, pain sensitivity measures will be re-assessed as described above.

Inclusion Criteria:

1. Not currently seeking treatment for pain past month;
2. between 18 - 75 years old.

Exclusion Criteria: Participants will not be excluded based on race or gender but will be excluded if they meet any of the following

1. non-English speaking;
2. systemic medical condition is known to affect sensation (i.e., diabetes);
3. regular use of prescription pain medication to manage pain;
4. current or history of chronic pain condition;
5. currently using blood thinning medication;
6. any blood clotting disorder such as hemophilia;
7. any contraindication to the application of ice or cold packs, such as uncontrolled hypertension, cold urticaria, cryoglobulinemia, paroxysmal cold hemoglobinuria, and circulatory compromise;
8. involved in vigorous physical activities like heavy lifting, digging, aerobics or fast bicycling.