The Role of Opioidergic Systems in Breathing Based Analgesia

June 7, 2019 updated by: Fadel Zeidan, University of California, San Diego

The Role of Endogenous Opioidergic Systems in Breathing Based Analgesia

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.

Study Overview

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

Interventional

Enrollment (Actual)

60

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Health Sciences

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 53 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
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 Names:
  • mental training
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.
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.
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.
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.
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.
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 Names:
  • mental training
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.
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.
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 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 Names:
  • mental training

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.

Up to 3 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Up to 3 weeks
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.
up to 3 weeks
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.
up to 3 weeks
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.
up to 3 weeks
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.
up to 3 weeks
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.
up to 3 weeks
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.
up to 3 weeks
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.
up to 3 weeks
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."
Up to 3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 13, 2017

Primary Completion (Actual)

June 27, 2017

Study Completion (Actual)

June 27, 2017

Study Registration Dates

First Submitted

January 16, 2018

First Submitted That Met QC Criteria

January 26, 2018

First Posted (Actual)

February 5, 2018

Study Record Updates

Last Update Posted (Actual)

June 11, 2019

Last Update Submitted That Met QC Criteria

June 7, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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