The Role of Opioidergic Systems in Breathing Based Analgesia

NCT03419858 | Completed Early Phase 1 FDA Drug

• 1 other identifier: IRB00040519
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Pain

Keywords

Pain; Slow-Breathing; Mindfulness; Opioids; Placebo

Outcome Measures

Primary Outcomes (1)

• 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.

  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 Outcomes (9)

• Respiration Rate Measures

  Up to 3 weeks

• State Anxiety Inventory

  up to 3 weeks

• Pain Catastrophizing Scale (PCS)

  up to 3 weeks

• Cohen Perceived Stress Scale (CPS)

  up to 3 weeks

• Treatment Effectiveness Scale

  up to 3 weeks

Study Arms (3)

Mindfulness Meditation Group

EXPERIMENTAL

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.

Behavioral: Mindfulness Meditation; Drug: Naloxone; Other: Saline

Placebo Meditation Group

ACTIVE COMPARATOR

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.

Behavioral: Placebo Meditation; Drug: Naloxone; Other: Saline

Slow-Breathing Group

ACTIVE COMPARATOR

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.

Behavioral: Slow-Breathing; Drug: Naloxone; Other: Saline

Interventions

Mindfulness Meditation BEHAVIORAL

A well-validated brief mindfulness-based mental training regimen \[four sessions; 20 min/session\] was used to teach patients to independently practice mindfulness meditation.

Also known as: mental training

Mindfulness Meditation Group

Placebo Meditation BEHAVIORAL

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.

Also known as: mental training

Placebo Meditation Group

Slow-Breathing BEHAVIORAL

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.

Also known as: mental training

Slow-Breathing Group

Naloxone DRUG

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.

Mindfulness Meditation Group; Placebo Meditation Group; Slow-Breathing Group

Saline OTHER

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.

Mindfulness Meditation Group; Placebo Meditation Group; Slow-Breathing Group

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, San Diego: lead

Study Sites (1)

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

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MeSH Terms

Conditions

Pain; Hypoventilation

Interventions

Mindfulness; Naloxone; Sodium Chloride

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Respiratory Insufficiency; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory

Intervention Hierarchy (Ancestors)

Cognitive Behavioral Therapy; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Fadel Zeidan, PhD

  Wake Forest University Health Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: 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.

Study Record Dates

• First Submitted: January 16, 2018
• First Posted: February 5, 2018
• Study Start: March 13, 2017
• Primary Completion: June 27, 2017
• Study Completion: June 27, 2017
• Last Updated: June 11, 2019

Record last verified: 2019-06

Locations

US (1)