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The Role of Opioidergic Systems in Breathing Based Analgesia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03419858
Recruitment Status : Completed
First Posted : February 5, 2018
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Fadel Zeidan, University of California, San Diego

Tracking Information
First Submitted Date  ICMJE January 16, 2018
First Posted Date  ICMJE February 5, 2018
Last Update Posted Date June 11, 2019
Actual Study Start Date  ICMJE March 13, 2017
Actual Primary Completion Date June 27, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2018)
Change in Visual Analog Scale Pain intensity and Unpleasantness ratings as a function of each respective cognitive manipulations and activation in response to naloxone and/or saline. [ Time Frame: Up to 3 weeks ]
The visual analog scale (VAS) measures pain ratings that are assessed in response to noxious (49°C) thermal stimuli applied to the back of the right calf muscle. Pain intensity and unpleasantness ratings will be assessed with a Visual Analog Scale. The minimum rating ("0") is designated as "no pain" whereas the maximum ("10") is labeled as "most intense imaginable" or "most unpleasant imaginable". Higher values corresponded to higher perceived pain ratings. Pain ratings were assessed at baseline (session 1) and again at sessions six and seven to determine the impact of the mental training regimens. At session six and seven, subjects were given an infusion of either naloxone or saline to address the potential contribution of the opioidergic system in the cognitive modulation of pain.
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
Change in the Visual Analog Scale Pain Ratings as a function of mental training and activation or inactivation (via. naloxone treatment) of opioid receptors. [ Time Frame: Up to 3 weeks ]
The visual analog scale (VAS) measures pain ratings that are assessed in response to noxious (49°C) thermal stimuli applied to the back of the right calf muscle. Pain intensity and unpleasantness ratings will be assessed with a Visual Analog Scale. The minimum rating ("0") is designated as "no pain" whereas the maximum ("10") is labeled as "most intense imaginable" or "most unpleasant imaginable". Higher values correspond to higher perceived pain ratings. Baseline pain ratings were assessed at session two and then measured again at sessions six and seven to determine the impact of the mental training regimens used. At session six or seven subjects were given an infusion of either naloxone (opioid receptors rendered inactivate) or saline (opioid receptors intact) to address the potential contribution of the opioidergic system in mediating mindfulness-based analgesia.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2019)
  • Respiration Rate Measures [ Time Frame: Up to 3 weeks ]
    A respiratory transducer (TSD 201; Biopac Systems) was placed around the chest to measure the participant's rate of respiration.
  • State Anxiety Inventory [ Time Frame: up to 3 weeks ]
    This inventory is a 20 question test used to measure a subject's state of anxiety. A numeric value between 1 (Not at all) and 4 (Very Much So) is provided in response to each statement. The range of scores for this test is between 20 and 80, with higher scores reflecting higher estimates of anxiety.
  • Pain Catastrophizing Scale (PCS) [ Time Frame: up to 3 weeks ]
    The PCS is a 13 item scale, with each item rated on a 5-point scale between: 0 (Not at all) and 4 (all the time). The PCS is broken into three subscales including: magnification, rumination, and helplessness. The total range of scores is between 0-52 with higher values reflecting more salient impacts of pain on one's day to day experience.
  • Cohen Perceived Stress Scale (CPS) [ Time Frame: up to 3 weeks ]
    The CPS is a series of 10 temporally constrained (i.e. in the last month) questions meant to ascertain the relative frequency of stressors in one's life, ranging from never (scored as 0) to very often (scored as 4). All positively stated questions are reversed scored and then all items are summed to yield a final estimate of stress. The higher the score the higher the level of stress.
  • Treatment Effectiveness Scale [ Time Frame: up to 3 weeks ]
    A VAS assessed the effectiveness of the study's intervention. Values on this scale vary continuously between 0 (not effective) and 10 (most effective imaginable). Higher values indicate a subject's greater confidence in the perceived treatment effectiveness.
  • Attitude Toward Treatment Scale (ATTS) [ Time Frame: up to 3 weeks ]
    The ATTS was used to monitor a participant's impressions and attitudes about the interventions used in this study. It supplies 5 multiple-choice questions answered on a 10 point scale, ranging from 0 (not logical) to 9 (very logical). Higher scores reflect more positive subject impressions about the therapeutic interventions.
  • Center for Epidemiological Studies Depression Scale (CES-D) [ Time Frame: up to 3 weeks ]
    This is a brief self-report questionnaire used to measure the severity of depressive symptoms. The CES-D is an inventory of 20 self-report items regarding depressive symptoms. Each question is graded on a 0 to 3 point scale with 0 representing "not at all" and 3 representing "a lot". Four questions (4,8,12, and 16) are reverse scored. A score of 15 or higher indicates a risk for depression.
  • Stress-Level Visual Analogue Scale [ Time Frame: up to 3 weeks ]
    A VAS was employed to measure subjective stress ratings. Values on this scale vary continuously between 0 (no stress) to 10 (most stress imaginable). Higher values indicate higher assessments of the subject's stress level.
  • Naloxone Symptom Assessments [ Time Frame: Up to 3 weeks ]
    A numerical ratings scale was used to assess potential naloxone related symptomology after each clinical research unit session. "0" was designated as "non-existent" and "6" was characterized as "extremely strong". We measured symptoms corresponding to "dry mouth, dry skin, blurred vision, sedation, nausea, dizziness, and headache."
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
  • Respiration Rate Measures [ Time Frame: Up to 3 weeks ]
    A respiratory transducer (TSD 201; Biopac Systems) was placed around the chest to measure the participant's rate of respiration.
  • State Anxiety Inventory [ Time Frame: up to 3 weeks ]
    This inventory is a 20 question test used to measure a subject's state of anxiety. A numeric value between 1 (Not at all) and 4 (Very Much So) is provided in response to each statement. The range of scores for this test is between 20 and 80, with higher scores reflecting higher estimates of anxiety.
  • Pain Catastrophizing Scale (PCS) [ Time Frame: up to 3 weeks ]
    The PCS is a 13 item scale, with each item rated on a 5-point scale between: 0 (Not at all) and 4 (all the time). The PCS is broken into three subscales including: magnification, rumination, and helplessness. The total range of scores is between 0-52 with higher values reflecting more salient impacts of pain on one's day to day experience.
  • Freiburg Mindfulness Inventory [ Time Frame: up to 3 weeks ]
    The FMI is a 14 item measure of mindfulness. Each declarative statement is measured on a 4 point scale ranging from: 1 Rarely to 4 Almost always. A couple of the items are reverse scored. Higher scores reflect higher states of mindfulness.
  • Cohen Perceived Stress Scale (CPS) [ Time Frame: up to 3 weeks ]
    The CPS is a series of 10 temporally constrained (i.e. in the last month) questions meant to ascertain the relative frequency of stressors in one's life, ranging from never (scored as 0) to very often (scored as 4). All positively stated questions are reversed scored and then all items are summed to yield a final estimate of stress. The higher the score the higher the level of stress.
  • Treatment Effectiveness Scale [ Time Frame: up to 3 weeks ]
    This is a case report form developed by this lab to rate a user's assessment of the effectiveness of the study's intervention (i.e. meditation and or slow breathing). These ratings are obtained using a visual analog scale. Values on this scale vary continuously between 0 (not effective) and 10 (most effective imaginable). Higher values indicate a subject's greater confidence in the perceived treatment effectiveness.
  • Attitude Toward Treatment Scale (ATTS) [ Time Frame: up to 3 weeks ]
    The ATTI is used to monitor a participant's impressions and attitudes about the interventions used in this study (i.e. mindfulness meditation). It supplies 5 multiple-choice questions answered on a 10 point scale, ranging from 0 (not logical) to 9 (very logical). Higher scores reflect more positive subject impressions about the therapeutic interventions.
  • Center for Epidemiological Studies Depression Scale (CES-D) [ Time Frame: up to 3 weeks ]
    This is a brief self-report questionnaire used to measure the severity of depressive symptoms. The CES-D is an inventory of 20 self-report items regarding depressive symptoms. Each question is graded on a 0 to 3 point scale with 0 representing "not at all" and 3 representing "a lot". Four questions (4,8,12, and 16) are reverse scored. A score of 15 or higher indicates a risk for depression.
  • Stress-Level Visual Analogue Scale [ Time Frame: up to 3 weeks ]
    This is a case report form developed by this lab to record user's stress assessment before an experimental session. The process uses a visual analog scale to quantify their stress level. Values on this scale vary continuously between 0 (no stress) to 10 (most stress imaginable). Higher values indicate higher assessments of the subject's stress level.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Role of Opioidergic Systems in Breathing Based Analgesia
Official Title  ICMJE The Role of Endogenous Opioidergic Systems in Breathing Based Analgesia
Brief Summary The purpose of this psychophysical and pharmacologic study is to determine if slow-breathing induced pain relief is mediated by endogenous opioids in response to intravenous (IV) administration of the opioid antagonist naloxone during noxious heat stimulation. We were also interested in disentangling the endogenous analgesic mechanisms supporting mindfulness-based analgesia.
Detailed Description The proposed study will employ a graded analytical approach to compare mindfulness to placebo-meditation and a slow-breathing exercise in response to double-blind intravenous administration (IV) of naloxone/placebo-saline and noxious heat stimulation. The aim of this study is to determine if slow-breathing induced analgesia is associated with the release of endogenous opioids. The proposed study will disentangle the specific stage of cognitive and/or respiration-based involvement (if any) of opioidergically mediated pain relief, a critical step in identifying the specific analgesic mechanisms corresponding to mindfulness based cognitive techniques.
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
The study employed a double blind 3x2x2 crossover factorial design. Baseline pain intensity and pain unpleasantness ratings were assessed using visual analog scales (11 point) obtained before and after four, 5-minute noxious heat stimulation series (49°C). Study volunteers (20/group; 60 total) were randomized and subsequently participated in a four session (20min/session) mindfulness meditation, placebo-meditation, or slow-breathing training regimen. After training completion, subjects reported to the Wake Forest Clinical Research Unit to test the study hypotheses across two separate experimental sessions. Half of the study volunteers (n=10) from each group were administered naloxone (opioid antagonist; 0.15 mg/kg bolus+ 0.1mg/kg/hour infusion) and in the subsequent session were administered IV placebo-saline and vice versa.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
Only the study physician, research coordinator, and research pharmacist were aware of drug assignments. Research staff (nurses; research technicians) and the PI were not blinded to drug assignment.
Primary Purpose: Basic Science
Condition  ICMJE Pain
Intervention  ICMJE
  • Behavioral: Mindfulness Meditation
    A well-validated brief mindfulness-based mental training regimen [four sessions; 20 min/session] was used to teach patients to independently practice mindfulness meditation.
    Other Name: mental training
  • Behavioral: Placebo Meditation
    A well-validated brief meditation-based mental training regimen [four sessions; 20 min/session] was used to teach patients to independently practice closing their eyes and take a deep breath every few minutes.
    Other Name: mental training
  • Behavioral: Slow-Breathing
    Study volunteers practiced lowering their breathing rate, across four, 20 minute training sessions, in response to a fluctuating light with the guidance of a trained facilitator.
    Other Name: mental training
  • Drug: Naloxone
    A 0.15 mg/kg bolus dose of naloxone (Naloxone Hydrichloride, Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, California) in 25ml normal saline was administered over 10 minutes. We also administered a supplementary IV infusion dose of 0.1mg/kg/hour naloxone immediately after bolus infusion ceased till the end of the experiment.
  • Other: Saline
    A 0.15 mg/kg bolus dose of saline in 25ml normal saline was administered over 10 minutes. We also administered a supplementary IV infusion dose of 0.1mg/kg/hour saline immediately after bolus infusion ceased till the end of the experiment.
Study Arms  ICMJE
  • Experimental: Mindfulness Meditation Group
    Subjects participated in four sessions (20 min/session) of mindfulness training. Participants were taught that perceived sensory events are "momentary" and "fleeting" and require no further evaluation. They were asked to close their eyes, relax and to focus on the flow of their breathing and "simply let go" of discursive thoughts.
    Interventions:
    • Behavioral: Mindfulness Meditation
    • Drug: Naloxone
    • Other: Saline
  • Active Comparator: Placebo Meditation Group
    The purpose of this intervention was to lead subjects to attend to one's breathing in a non-evaluative manner. Subjects were instructed to sit with a straight posture, closed eyes, and to take a deep, slow breaths every 2-3 minutes.
    Interventions:
    • Behavioral: Placebo Meditation
    • Drug: Naloxone
    • Other: Saline
  • Active Comparator: Slow-Breathing Group
    A validated (Chalaye et al., 2009) slow breathing training regimen was employed, using fluctuating light, to teach individuals to independently lower their respective respiration rate. Subjects practiced lowering their respiration rates across four, 20 minute sessions.
    Interventions:
    • Behavioral: Slow-Breathing
    • Drug: Naloxone
    • Other: Saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 26, 2018)
60
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 27, 2017
Actual Primary Completion Date June 27, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Normal volunteers with no history of chronic pain problems
  • Volunteers had no prior meditation experience
  • Volunteers could be male and non-pregnant females.
  • Volunteers of all ethnic backgrounds were included.

Exclusion Criteria:

  • Female volunteers could not be pregnant.
  • They could not be taking opioids or antidepressants.
  • Subjects with a repeated history of syncope, loss of consciousness, light headedness, nausea, dizziness, or vomiting in response to needles or blood could not participate in the study.
  • Subject could not be using exogenous opiates for the complete duration of the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03419858
Other Study ID Numbers  ICMJE IRB00040519
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fadel Zeidan, University of California, San Diego
Study Sponsor  ICMJE University of California, San Diego
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Fadel Zeidan, PhD Wake Forest University Health Sciences
PRS Account University of California, San Diego
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP