- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03419858
The Role of Opioidergic Systems in Breathing Based Analgesia
The Role of Endogenous Opioidergic Systems in Breathing Based Analgesia
Study Overview
Status
Conditions
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
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North Carolina
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Winston-Salem, North Carolina, United States, 27157
- Wake Forest University Health Sciences
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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.
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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:
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.
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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.
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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:
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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:
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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
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A respiratory transducer (TSD 201; Biopac Systems) was placed around the chest to measure the participant's rate of respiration.
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Up to 3 weeks
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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.
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up to 3 weeks
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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
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Cohen Perceived Stress Scale (CPS)
Time Frame: up to 3 weeks
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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.
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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.
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up to 3 weeks
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Center for Epidemiological Studies Depression Scale (CES-D)
Time Frame: up to 3 weeks
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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.
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up to 3 weeks
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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.
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up to 3 weeks
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Naloxone Symptom Assessments
Time Frame: Up to 3 weeks
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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."
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Up to 3 weeks
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Collaborators and Investigators
Publications and helpful links
General Publications
- Ludwig DS, Kabat-Zinn J. Mindfulness in medicine. JAMA. 2008 Sep 17;300(11):1350-2. doi: 10.1001/jama.300.11.1350. No abstract available.
- Zeidan F, Gordon NS, Merchant J, Goolkasian P. The effects of brief mindfulness meditation training on experimentally induced pain. J Pain. 2010 Mar;11(3):199-209. doi: 10.1016/j.jpain.2009.07.015. Epub 2009 Oct 22.
- Zeidan F, Martucci KT, Kraft RA, Gordon NS, McHaffie JG, Coghill RC. Brain mechanisms supporting the modulation of pain by mindfulness meditation. J Neurosci. 2011 Apr 6;31(14):5540-8. doi: 10.1523/JNEUROSCI.5791-10.2011.
- Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985 Jun;8(2):163-90. doi: 10.1007/BF00845519.
- Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron. 2007 Aug 2;55(3):377-91. doi: 10.1016/j.neuron.2007.07.012.
- Lutz A, Slagter HA, Dunne JD, Davidson RJ. Attention regulation and monitoring in meditation. Trends Cogn Sci. 2008 Apr;12(4):163-9. doi: 10.1016/j.tics.2008.01.005. Epub 2008 Mar 10.
- Zeidan F, Adler-Neal AL, Wells RE, Stagnaro E, May LM, Eisenach JC, McHaffie JG, Coghill RC. Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids. J Neurosci. 2016 Mar 16;36(11):3391-7. doi: 10.1523/JNEUROSCI.4328-15.2016.
- Zeidan F, Emerson NM, Farris SR, Ray JN, Jung Y, McHaffie JG, Coghill RC. Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia. J Neurosci. 2015 Nov 18;35(46):15307-25. doi: 10.1523/JNEUROSCI.2542-15.2015.
- Zeidan F, Johnson SK, Diamond BJ, David Z, Goolkasian P. Mindfulness meditation improves cognition: evidence of brief mental training. Conscious Cogn. 2010 Jun;19(2):597-605. doi: 10.1016/j.concog.2010.03.014. Epub 2010 Apr 3.
- Zeidan F, Johnson SK, Gordon NS, Goolkasian P. Effects of brief and sham mindfulness meditation on mood and cardiovascular variables. J Altern Complement Med. 2010 Aug;16(8):867-73. doi: 10.1089/acm.2009.0321.
- Zeidan F, Martucci KT, Kraft RA, McHaffie JG, Coghill RC. Neural correlates of mindfulness meditation-related anxiety relief. Soc Cogn Affect Neurosci. 2014 Jun;9(6):751-9. doi: 10.1093/scan/nst041. Epub 2013 Apr 24.
- Cusens B, Duggan GB, Thorne K, Burch V. Evaluation of the breathworks mindfulness-based pain management programme: effects on well-being and multiple measures of mindfulness. Clin Psychol Psychother. 2010 Jan-Feb;17(1):63-78. doi: 10.1002/cpp.653.
- Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005 Aug;9(4):463-84. doi: 10.1016/j.ejpain.2004.11.001. Epub 2005 Jan 21.
- Bertisch SM, Wee CC, Phillips RS, McCarthy EP. Alternative mind-body therapies used by adults with medical conditions. J Psychosom Res. 2009 Jun;66(6):511-9. doi: 10.1016/j.jpsychores.2008.12.003. Epub 2009 Mar 3.
- Borras MC, Becerra L, Ploghaus A, Gostic JM, DaSilva A, Gonzalez RG, Borsook D. fMRI measurement of CNS responses to naloxone infusion and subsequent mild noxious thermal stimuli in healthy volunteers. J Neurophysiol. 2004 Jun;91(6):2723-33. doi: 10.1152/jn.00249.2003.
- Brown CA, Jones AKP. Meditation experience predicts less negative appraisal of pain: electrophysiological evidence for the involvement of anticipatory neural responses. Pain. 2010 Sep;150(3):428-438. doi: 10.1016/j.pain.2010.04.017. Epub 2010 May 21.
- Chalaye P, Goffaux P, Lafrenaye S, Marchand S. Respiratory effects on experimental heat pain and cardiac activity. Pain Med. 2009 Nov;10(8):1334-40. doi: 10.1111/j.1526-4637.2009.00681.x. Epub 2009 Aug 7.
- Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002-2012. Natl Health Stat Report. 2015 Feb 10;(79):1-16.
- Coghill RC, McHaffie JG, Yen YF. Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8538-42. doi: 10.1073/pnas.1430684100. Epub 2003 Jun 24. Erratum In: Proc Natl Acad Sci U S A. 2017 Nov 20;:. Yen, Ye-Fen [corrected to Yen, Yi-Fen].
- Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, Buchel C. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009 Aug 27;63(4):533-43. doi: 10.1016/j.neuron.2009.07.014.
- Friesner SA, Curry DM, Moddeman GR. Comparison of two pain-management strategies during chest tube removal: relaxation exercise with opioids and opioids alone. Heart Lung. 2006 Jul-Aug;35(4):269-76. doi: 10.1016/j.hrtlng.2005.10.005.
- Grant JA, Rainville P. Pain sensitivity and analgesic effects of mindful states in Zen meditators: a cross-sectional study. Psychosom Med. 2009 Jan;71(1):106-14. doi: 10.1097/PSY.0b013e31818f52ee. Epub 2008 Dec 10.
- Grant JA, Courtemanche J, Duerden EG, Duncan GH, Rainville P. Cortical thickness and pain sensitivity in zen meditators. Emotion. 2010 Feb;10(1):43-53. doi: 10.1037/a0018334.
- Grill JD, Coghill RC. Transient analgesia evoked by noxious stimulus offset. J Neurophysiol. 2002 Apr;87(4):2205-8. doi: 10.1152/jn.00730.2001.
- Kabat-Zinn J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychiatry. 1982 Apr;4(1):33-47. doi: 10.1016/0163-8343(82)90026-3.
- Koyama T, McHaffie JG, Laurienti PJ, Coghill RC. The single-epoch fMRI design: validation of a simplified paradigm for the collection of subjective ratings. Neuroimage. 2003 Jul;19(3):976-87. doi: 10.1016/s1053-8119(03)00119-8.
- MacLean KA, Ferrer E, Aichele SR, Bridwell DA, Zanesco AP, Jacobs TL, King BG, Rosenberg EL, Sahdra BK, Shaver PR, Wallace BA, Mangun GR, Saron CD. Intensive meditation training improves perceptual discrimination and sustained attention. Psychol Sci. 2010 Jun;21(6):829-39. doi: 10.1177/0956797610371339. Epub 2010 May 11.
- Martin SL, Kerr KL, Bartley EJ, Kuhn BL, Palit S, Terry EL, DelVentura JL, Rhudy JL. Respiration-induced hypoalgesia: exploration of potential mechanisms. J Pain. 2012 Aug;13(8):755-63. doi: 10.1016/j.jpain.2012.05.001. Epub 2012 Jul 4.
- Martucci KT, Eisenach JC, Tong C, Coghill RC. Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information. Pain. 2012 Jun;153(6):1232-1243. doi: 10.1016/j.pain.2012.02.035. Epub 2012 Apr 13.
- Mehling WE, Hamel KA, Acree M, Byl N, Hecht FM. Randomized, controlled trial of breath therapy for patients with chronic low-back pain. Altern Ther Health Med. 2005 Jul-Aug;11(4):44-52.
- Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science. 2000 Jun 9;288(5472):1769-72. doi: 10.1126/science.288.5472.1769.
- Price DD, McHaffie JG, Larson MA. Spatial summation of heat-induced pain: influence of stimulus area and spatial separation of stimuli on perceived pain sensation intensity and unpleasantness. J Neurophysiol. 1989 Dec;62(6):1270-9. doi: 10.1152/jn.1989.62.6.1270.
- Price DD, Bush FM, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain. 1994 Feb;56(2):217-226. doi: 10.1016/0304-3959(94)90097-3.
- Rhudy JL. Respiration-induced hypoalgesia: additional evidence for pain modulation deficits in fibromyalgia? Pain. 2010 Apr;149(1):1-2. doi: 10.1016/j.pain.2010.01.004. Epub 2010 Feb 1. No abstract available.
- Rosier EM, Iadarola MJ, Coghill RC. Reproducibility of pain measurement and pain perception. Pain. 2002 Jul;98(1-2):205-16. doi: 10.1016/s0304-3959(02)00048-9.
- Schoell ED, Bingel U, Eippert F, Yacubian J, Christiansen K, Andresen H, May A, Buechel C. The effect of opioid receptor blockade on the neural processing of thermal stimuli. PLoS One. 2010 Aug 27;5(8):e12344. doi: 10.1371/journal.pone.0012344.
- Stone CI, Demchik-Stome DA, Horan JJ. Coping with pain: a component analysis of Lamaze and cognitive-behavioral procedures. J Psychosom Res. 1977;21(6):451-6. doi: 10.1016/0022-3999(77)90067-8. No abstract available.
- Wells RE, Bertisch SM, Buettner C, Phillips RS, McCarthy EP. Complementary and alternative medicine use among adults with migraines/severe headaches. Headache. 2011 Jul-Aug;51(7):1087-97. doi: 10.1111/j.1526-4610.2011.01917.x. Epub 2011 Jun 7.
- Zautra AJ, Fasman R, Davis MC, Craig ADB. The effects of slow breathing on affective responses to pain stimuli: an experimental study. Pain. 2010 Apr;149(1):12-18. doi: 10.1016/j.pain.2009.10.001. Epub 2010 Jan 15.
- Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci. 2005 Aug 24;25(34):7754-62. doi: 10.1523/JNEUROSCI.0439-05.2005.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- IRB00040519
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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