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Effects of Mindfulness-Oriented Intervention on Endogenous Opioid Mechanisms of Hedonic Regulation in Chronic Pain

Principal Investigator (PI) / Project Lead:


Funding Organization:

National Institute of Health, National Center for Complementary & Integrative Health

RFP / FOA Number:


Award Number:


Funding Period:

9/16/2016 – 6/10/2019

Total Funding:

$ 830,946

Project Status:



Project Description:

Chronic pain is often treated with extended use of opioid analgesics, yet these drugs can alter the brain in ways that make it difficult to cope with pain and experience pleasure in life. Meditation-based interventions may be an effective means of addressing these issues, but research is needed to understand how such interventions change the brain to reduce suffering. The objective of the proposed project is to study the effects of an innovative meditation intervention on brain mechanisms linked with pain and pleasure.



Chronic pain is typically managed with extended use of opioid analgesics, despite an absence of data on their long-term efficacy and clear evidence of significant health risks. Prolonged opioid use dysregulates the endogenous opioid system, disrupting hedonic homeostasis in the brain and resulting in hyperalgesia, stress reactivity, and reward insensitivity – factors that exacerbate chronic pain and increase risk for opioid misuse. Thus, chronic pain patients receiving extended opioid therapy suffer from impaired regulation of aversive (e.g., pain) and appetitive experience (e.g., pleasure), dual processes subserved by opioid-mediated, hedonic regulatory mechanisms. However, according to a 2015 NIH systematic review, there are no interventions with proven efficacy for improving outcomes among chronic pain patients on long-term opioid therapy. Extant therapies may have limited efficacy because they fail to directly target the neural circuits of hedonic regulation. In contrast, meditation-based interventions, which have been conceptualized as means of self-regulating hedonic function, may hold promise for addressing this public health concern. The overarching aim of this proposal is to determine the capacity of a novel meditation intervention, Mindfulness-Oriented Recovery Enhancement (MORE), to restore endogenous opioid system function as measured with PET and a selective μ-opioid radiotracer. In the R61, we will compare the effects of MORE to a support group (SG) control on measures of endogenous opioid system function during sustained muscle pain, and will use fMRI and behavioral measures to assess whether changes in opioid function are associated with improved regulation of appetitive (reward) and aversive (pain) experience among chronic non-neuropathic back pain patients (CNBP). In the R33, we will further validate the opioid functional mechanism by examining the A118G allele of the μ-opioid receptor gene (which has been linked to low μ-opioid function, hyperalgesia, and insensitivity to opioid analgesia) as a moderator of MORE’s effects on the endogenous opioid system, fMRI measures of natural reward responsiveness, and clinical outcomes – including pain and opioid use. Furthermore, to refine our understanding of how the intervention modulates these neural mechanisms, the R33 will assess the dose of meditation skill practice as a predictor of changes in endogenous opioid function and clinical correlates. This multi-PI proposal unites expertise in meditation-based interventions with expertise in neurogenetics and the use of PET and fMRI to probe the neurobiological mechanisms of pain and affective experience, and builds upon a program of prior research which provided preliminary efficacy data on the MORE intervention and standardized its delivery via manualization of the treatment and development of fidelity measures. By elucidating a key mechanism of this meditation-based intervention, the proposed translational research will enable rapid optimization of MORE for Stage III clinical trial implementation and dissemination, allowing us to provide a timely solution to this public health problem of escalating significance.


Publications (27, sorted by newest to oldest):

  1. Hanley AW, Dambrun M, Garland EL. Effects of Mindfulness Meditation on Self-Transcendent States: Perceived Body Boundaries and Spatial Frames of Reference. Mindfulness (N Y). 2020 May;11(5):1194-1203. doi: 1007/s12671-020-01330-9. Epub 2020 Feb 14. PMID: 33747250; PMCID: PMC7968136.


  1. Garland EL, Hudak J, Hanley AW, Nakamura Y. Mindfulness-oriented recovery enhancement reduces opioid dose in primary care by strengthening autonomic regulation during meditation. Am Psychol. 2020 Sep;75(6):840-852. doi: 1037/amp0000638. PMID: 32915027; PMCID: PMC7490853.


  1. Garland EL, Atchley RM, Hanley AW, Zubieta JK, Froeliger B. Mindfulness-Oriented Recovery Enhancement remediates hedonic dysregulation in opioid users: Neural and affective evidence of target engagement. Sci Adv. 2019 Oct 16;5(10):eaax1569. doi: 1126/sciadv.aax1569. PMID: 31663023; PMCID: PMC6795512.


  1. Garland EL, Hanley AW, Riquino MR, Reese SE, Baker AK, Salas K, Yack BP, Bedford CE, Bryan MA, Atchley R, Nakamura Y, Froeliger B, Howard MO. Mindfulness-oriented recovery enhancement reduces opioid misuse risk via analgesic and positive psychological mechanisms: A randomized controlled trial. J Consult Clin Psychol. 2019 Oct;87(10):927-940. doi: 1037/ccp0000390. PMID: 31556669; PMCID: PMC6764586.


  1. Hanley AW, Garland EL. Mapping the Affective Dimension of Embodiment With the Sensation Manikin: Validation Among Chronic Pain Patients and Modification by Mindfulness-Oriented Recovery Enhancement. Psychosom Med. 2019 Sep;81(7):612-621. doi: 1097/PSY.0000000000000725. PMID: 31246748.


  1. Thomas EA, Mijangos JL, Hansen PA, White S, Walker D, Reimers C, Beck AC, Garland EL. Mindfulness-Oriented Recovery Enhancement Restructures Reward Processing and Promotes Interoceptive Awareness in Overweight Cancer Survivors: Mechanistic Results From a Stage 1 Randomized Controlled Trial. Integr Cancer Ther. 2019 Jan-Dec;18:1534735419855138. doi: 1177/1534735419855138. PMID: 31165653; PMCID: PMC6552347.


  1. Garland EL, Reese SE, Bedford CE, Baker AK. Adverse childhood experiences predict autonomic indices of emotion dysregulation and negative emotional cue-elicited craving among female opioid-treated chronic pain patients. Dev Psychopathol. 2019 Aug;31(3):1101-1110. doi: 1017/S0954579419000622. Epub 2019 May 7. PMID: 31060644.


  1. McConnell PA, Garland EL, Zubieta JK, Newman-Norlund R, Powers S, Froeliger B. Impaired frontostriatal functional connectivity among chronic opioid using pain patients is associated with dysregulated affect. Addict Biol. 2020 Mar;25(2):e12743. doi: 1111/adb.12743. Epub 2019 Apr 4. PMID: 30945801; PMCID: PMC6776713.


  1. Hanley AW, Garland EL. Mindfulness training disrupts Pavlovian conditioning. Physiol Behav. 2019 May 15;204:151-154. doi: 1016/j.physbeh.2019.02.028. Epub 2019 Feb 23. PMID: 30807770.


  1. Garland EL, Fredrickson BL. Positive psychological states in the arc from mindfulness to self-transcendence: extensions of the Mindfulness-to-Meaning Theory and applications to addiction and chronic pain treatment. Curr Opin Psychol. 2019 Aug;28:184-191. doi: 1016/j.copsyc.2019.01.004. Epub 2019 Jan 14. PMID: 30763873; PMCID: PMC6626690.


  1. Garland EL, Bryan MA, Priddy SE, Riquino MR, Froeliger B, Howard MO. Effects of Mindfulness-Oriented Recovery Enhancement Versus Social Support on Negative Affective Interference During Inhibitory Control Among Opioid-Treated Chronic Pain Patients: A Pilot Mechanistic Study. Ann Behav Med. 2019 Aug 29;53(10):865-876. doi: 1093/abm/kay096. PMID: 30668631; PMCID: PMC6735955.


  1. Baker AK, Garland EL. Autonomic and affective mediators of the relationship between mindfulness and opioid craving among chronic pain patients. Exp Clin Psychopharmacol. 2019 Feb;27(1):55-63. doi: 1037/pha0000225. Epub 2018 Sep 27. PMID: 30265061; PMCID: PMC6355352.


  1. Hanley AW, Nakamura Y, Garland EL. The Nondual Awareness Dimensional Assessment (NADA): New tools to assess nondual traits and states of consciousness occurring within and beyond the context of meditation. Psychol Assess. 2018 Dec;30(12):1625-1639. doi: 1037/pas0000615. Epub 2018 Jul 30. PMID: 30058824; PMCID: PMC6265073.


  1. Garland EL, Hanley AW, Bedford CE, Zubieta JK, Howard MO, Nakamura Y, Donaldson GW, Froeliger B. Reappraisal deficits promote craving and emotional distress among chronic pain patients at risk for prescription opioid misuse. J Addict Dis. 2018 Jan-Jun;37(1-2):14-22. doi: 1080/10550887.2018.1459148. Epub 2018 Jun 4. PMID: 29863439.


  1. Hanley AW, Baker AK, Garland EL. The Mindful Personality II: Exploring the Metatraits from a Cybernetic Perspective. Mindfulness (N Y). 2018 Jun;9(3):972-979. doi: 1007/s12671-017-0836-5. Epub 2017 Oct 24. PMID: 29861793; PMCID: PMC5979271.



  1. Garland EL, Howard MO. Mindfulness-based treatment of addiction: current state of the field and envisioning the next wave of research. Addict Sci Clin Pract. 2018 Apr 18;13(1):14. doi: 1186/s13722-018-0115-3. PMID: 29669599; PMCID: PMC5907295.


  1. Garland EL, Bryan CJ, Kreighbaum L, Nakamura Y, Howard MO, Froeliger B. Prescription opioid misusing chronic pain patients exhibit dysregulated context-dependent associations: Investigating associative learning in addiction with the cue-primed reactivity task. Drug Alcohol Depend. 2018 Jun 1;187:13-21. doi: 1016/j.drugalcdep.2018.02.014. Epub 2018 Mar 27. PMID: 29626741.


  1. Li W, Garland EL, Howard MO. Therapeutic mechanisms of Mindfulness-Oriented Recovery Enhancement for internet gaming disorder: Reducing craving and addictive behavior by targeting cognitive processes. J Addict Dis. 2018 Jan-Jun;37(1-2):5-13. doi: 1080/10550887.2018.1442617. Epub 2018 Mar 22. PMID: 29565776.


  1. Hanley AW, Garland EL. The mindful personality: A meta-analysis from a cybernetic perspective. Mindfulness (N Y). 2017 Dec;8(6):1456-1470. doi: 1007/s12671-017-0736-8. Epub 2017 Jun 17. PMID: 29479377; PMCID: PMC5822739.


  1. Garland EL, Hanley AW, Goldin PR, Gross JJ. Testing the mindfulness-to-meaning theory: Evidence for mindful positive emotion regulation from a reanalysis of longitudinal data. PLoS One. 2017 Dec 6;12(12):e0187727. doi: 1371/journal.pone.0187727. PMID: 29211754; PMCID: PMC5718463.


  1. Hanley AW, Baker AK, Garland EL. Self-interest may not be entirely in the interest of the self: Association between selflessness, dispositional mindfulness and psychological well-being. Pers Individ Dif. 2017 Oct 15;117:166-171. doi: 1016/j.paid.2017.05.045. Epub 2017 Jun 8. PMID: 29200545; PMCID: PMC5703599.


  1. Garland EL, Hanley AW, Baker AK, Howard MO. Biobehavioral Mechanisms of Mindfulness as a Treatment for Chronic Stress: An RDoC Perspective. Chronic Stress (Thousand Oaks). 2017 Feb;1:2470547017711912. doi: 1177/2470547017711912. Epub 2017 Jun 22. PMID: 28840198; PMCID: PMC5565157.


  1. Hanley AW, Mehling WE, Garland EL. Holding the body in mind: Interoceptive awareness, dispositional mindfulness and psychological well-being. J Psychosom Res. 2017 Aug;99:13-20. doi: 1016/j.jpsychores.2017.05.014. Epub 2017 May 18. PMID: 28712417; PMCID: PMC5522814.


  1. Garland EL, Baker AK, Larsen P, Riquino MR, Priddy SE, Thomas E, Hanley AW, Galbraith P, Wanner N, Nakamura Y. Randomized Controlled Trial of Brief Mindfulness Training and Hypnotic Suggestion for Acute Pain Relief in the Hospital Setting. J Gen Intern Med. 2017 Oct;32(10):1106-1113. doi: 1007/s11606-017-4116-9. Epub 2017 Jul 12. PMID: 28702870; PMCID: PMC5602767.


  1. Garland EL, Howard MO, Zubieta JK, Froeliger B. Restructuring Hedonic Dysregulation in Chronic Pain and Prescription Opioid Misuse: Effects of Mindfulness-Oriented Recovery Enhancement on Responsiveness to Drug Cues and Natural Rewards. Psychother Psychosom. 2017;86(2):111-112. doi: 1159/000453400. Epub 2017 Feb 10. PMID: 28183077; PMCID: PMC5331925.


  1. Li W, Howard MO, Garland EL, McGovern P, Lazar M. Mindfulness treatment for substance misuse: A systematic review and meta-analysis. J Subst Abuse Treat. 2017 Apr;75:62-96. doi: 1016/j.jsat.2017.01.008. Epub 2017 Jan 31. PMID: 28153483.


  1. Garland EL, Bryan CJ, Nakamura Y, Froeliger B, Howard MO. Deficits in autonomic indices of emotion regulation and reward processing associated with prescription opioid use and misuse. Psychopharmacology (Berl). 2017 Feb;234(4):621-629. doi: 1007/s00213-016-4494-4. Epub 2016 Dec 8. PMID: 27933366; PMCID: PMC5266620.


For a complete list of publications supported by this grant, go to



Although the experiments proposed were not carried out due to problems with manufacturing the chemicals needed for PET neuroimaging, the positive emotion regulation task built for the fMRI portion of this study has already yielded useful data suggesting that chronic pain patients receiving long-term opioid therapy have blunted brain responses to naturally rewarding objects and events. This blunting during positive emotion regulation is an important risk factor that should be targeted by future interventions for people with chronic pain receiving long-term opioid therapy.

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Last Updated: 2/2/22