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The role of endogenous opioids in mindfulness and sham mindfulness-meditation for the direct alleviation of evoked chronic low back pain: a randomized clinical trial

Neuropsychopharmacology (2023)Cite this article

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Abstract

Chronic low back pain (cLBP) is the most prevalent chronic pain condition. There are no treatments that haven been found to directly assuage evoked cLBP. To this extent, mindfulness-meditation is a promising pain therapy. Yet, it is unclear if meditation can be utilized to directly attenuate evoked chronic pain through endogenous opioids. A double-blind, randomized, and placebo-controlled clinical trial with a drug crossover design examined if mindfulness-meditation, as compared to sham mindfulness-meditation, attenuated straight leg-raise test evoked chronic pain during intravenous (0.15 mg/kg bolus + 0.15 mg/kg/hour maintenance) naloxone (opioid antagonist) and placebo-saline infusion. Fifty-nine individuals with cLBP (mean age = 46 years; 30 females) completed all study procedures. After the pre-intervention pain testing session, patients were randomized to a four-session (20-min/session) mindfulness (n = 30) or sham mindfulness-meditation (n = 29) intervention. After the interventions, mindfulness and sham mindfulness-meditation were associated with significant reductions in back pain during saline and naloxone infusion when compared to rest (non-meditation) in response to the cLBP-evoking straight leg-raise test. These results indicate that meditation directly reduces evoked chronic pain through non-opioidergic processes. Importantly, after the interventions, the mindfulness group reported significantly lower straight leg-raise induced pain than the sham mindfulness-meditation group during rest (non-meditation) and meditation. Mindfulness and sham mindfulness-meditation training was also associated with significantly lower Brief Pain Inventory severity and interference scores. The pain-relieving effects of mindfulness meditation were more pronounced than a robust sham-mindfulness meditation intervention, suggesting that non-reactive appraisal processes may be uniquely associated with improvements in chronic low-back pain.

Trial Registration: ClinicalTrials.gov identifier: NCT04034004

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Fig. 1: Study design.
Fig. 2: Pain ratings in response to lying supine and straight leg-raise test across participants.
Fig. 3: Mindfulness and sham mindfulness-meditation group-based pain ratings in response to lying supine and straight leg-raise test during experimental sessions.

References

  1. Andersson GB. Epidemiological features of chronic low-back pain. lancet. 1999;354:581–5.

    Article  CAS  PubMed  Google Scholar 

  2. Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat Rev Rheumatol. 2010;6:599–606.

    Article  PubMed  Google Scholar 

  3. Corbett DB, Simon CB, Manini TM, George SZ, Riley JL III, Fillingim RB. Movement-evoked pain: transforming the way we understand and measure pain. Pain. 2019;160:757.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Esteve R, Ramírez-Maestre C, López-Martínez AE. Adjustment to chronic pain: the role of pain acceptance, coping strategies, and pain-related cognitions. Ann Behav Med. 2007;33:179–88.

    Article  PubMed  Google Scholar 

  5. Cherkin DC, Sherman KJ, Balderson BH, Cook AJ, Anderson ML, Hawkes RJ, et al. Effect of mindfulness-based stress reduction vs cognitive behavioral therapy or usual care on back pain and functional limitations in adults with chronic low back pain: a randomized clinical trial. JAMA. 2016;315:1240–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wells RE, O’Connell N, Pierce CR, Estave P, Penzien DB, Loder E, et al. Effectiveness of mindfulness meditation vs headache education for adults with migraine: a randomized clinical trial. JAMA Intern Med. 2021;181:317–28.

    Article  PubMed  Google Scholar 

  7. Colloca L, Petrovic P, Wager TD, Ingvar M, Benedetti F. How the number of learning trials affects placebo and nocebo responses. Pain®. 2010;151:430–39.

    Article  PubMed  Google Scholar 

  8. De Pascalis V, Chiaradia C, Carotenuto E. The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting. Pain. 2002;96:393–402.

    Article  PubMed  Google Scholar 

  9. Kaptchuk TJ. The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med. 2002;136:817–25.

    Article  PubMed  Google Scholar 

  10. Wager TD, Atlas LY, Leotti LA, Rilling JK. Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J Neurosci. 2011;31:439–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zeidan F, Johnson SK, Gordon NS, Goolkasian P. Effects of brief and sham mindfulness meditation on mood and cardiovascular variables. J Alter Complement Med. 2010;16:867–73.

    Article  Google Scholar 

  12. Zeidan F, Emerson NM, Farris SR, Ray JN, Jung Y, McHaffie JG, et al. Mindfulness meditation-based pain relief employs different neural mechanisms than placebo and sham mindfulness meditation-induced analgesia. J Neurosci. 2015;35:15307–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wells RE, Collier J, Posey G, Morgan A, Auman T, Strittmatter B, et al. Attention to breath sensations does not engage endogenous opioids to reduce pain. Pain. 2020;161:1884–93.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Adler-Neal AL, Waugh CE, Garland EL, Shaltout HA, Diz DI, Zeidan F. The role of heart rate variability in mindfulness-based pain relief. J pain. 2020;21:306–23.

    Article  PubMed  Google Scholar 

  15. Zubieta J-K, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293:311–15.

    Article  CAS  PubMed  Google Scholar 

  16. Mayer DJ, Price DD, Rafii A. Antagonism of acupuncture analgesia in man by the narcotic antagonist naloxone. Brain Res. 1977;121:368–72.

    Article  CAS  PubMed  Google Scholar 

  17. Watkins LR, Mayer DJ. Organization of endogenous opiate and nonopiate pain control systems. Science. 1982;216:1185–92.

    Article  CAS  PubMed  Google Scholar 

  18. Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63:533–43.

    Article  CAS  PubMed  Google Scholar 

  19. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet. 1978;2:654–7.

    Article  CAS  PubMed  Google Scholar 

  20. Zubieta J-K, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, et al. Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. J Neurosci. 2005;25:7754–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sprenger C, Eippert F, Finsterbusch J, Bingel U, Rose M, Büchel C. Attention modulates spinal cord responses to pain. Curr Biol. 2012;22:1019–22.

    Article  CAS  PubMed  Google Scholar 

  22. Taylor JJ, Borckardt JJ, Canterberry M, Li X, Hanlon CA, Brown TR, et al. Naloxone-reversible modulation of pain circuitry by left prefrontal rTMS. Neuropsychopharmacology. 2013;38:1189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Oliva V, Hartley-Davies R, Moran R, Pickering AE, Brooks JC. Simultaneous brain, brainstem, and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia. Elife. 2022;11:e71877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zeidan F, Adler-Neal AL, Wells RE, Stagnaro E, May LM, Eisenach JC, et al. Mindfulness-meditation-based pain relief is not mediated by endogenous opioids. J Neurosci. 2016;36:3391–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Martikainen IK, Pecina M, Love TM, Nuechterlein EB, Cummiford CM, Green CR, et al. Alterations in endogenous opioid functional measures in chronic back pain. J Neurosci. 2013;33:14729–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta J-K. Decreased central μ-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27:10000–06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bruehl S, Chung OY, Burns JW, Diedrich L. Trait anger expressiveness and pain-induced beta-endorphin release: support for the opioid dysfunction hypothesis. Pain. 2007;130:208–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Thompson SJ, Pitcher MH, Stone LS, Tarum F, Niu G, Chen X, et al. Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat. Pain. 2018;159:1856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schrepf A, Harper DE, Harte SE, Wang H, Ichesco E, Hampson JP, et al. Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study. Pain. 2016;157:2217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Willoch F, Schindler F, Wester HJ, Empl M, Straube A, Schwaiger M, et al. Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C] diprenorphine PET study. Pain. 2004;108:213–20.

    Article  CAS  PubMed  Google Scholar 

  31. Wasan AD, Loggia ML, Chen LQ, Napadow V, Kong J, Gollub RL. Neural correlates of chronic low back pain measured by arterial spin labeling. J Am Soc Anesthesiologists. 2011;115:364–74.

    Google Scholar 

  32. May LM, Kosek P, Zeidan F, Berkman ET. Enhancement of meditation analgesia by opioid antagonist in experienced meditators. Psychosom Med. 2018;80:807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Loggia ML, Kim J, Gollub RL, Vangel MG, Kirsch I, Kong J, et al. Default mode network connectivity encodes clinical pain: an arterial spin labeling study. PAIN®. 2013;154:24–33.

    Article  PubMed  Google Scholar 

  34. Cleeland CS, Ryan K. Pain assessment: global use of the Brief Pain Inventory. Annals of the Academy of Medicine, Singapore. 1994;23:129–38.

  35. Sullivan MJ, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychological Assess. 1995;7:524.

    Article  Google Scholar 

  36. Roland M, Morris R. A study of the natural history of low-back pain: part II: development of guidelines for trials of treatment in primary care. Spine. 1983;8:145–50.

    Article  CAS  PubMed  Google Scholar 

  37. Trøstheim M, Eikemo M, Haaker J, Frost JJ, Leknes S. Opioid antagonism in humans: a primer on optimal dose and timing for central mu-opioid receptor blockade. Neuropsychopharmacology. 2023;48:299–307.

    Article  PubMed  Google Scholar 

  38. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113:9–19.

    Article  PubMed  Google Scholar 

  39. Garland EL, Gaylord SA, Palsson O, Faurot K, Douglas Mann J, Whitehead WE. Therapeutic mechanisms of a mindfulness-based treatment for IBS: effects on visceral sensitivity, catastrophizing, and affective processing of pain sensations. J Behav Med. 2012;35:591–602.

    Article  PubMed  Google Scholar 

  40. Harrison R, Zeidan F, Kitsaras G, Ozcelik D, Salomons TV. Trait mindfulness is associated with lower pain reactivity and connectivity of the default mode network. J Pain. 2019;20:645–54.

    Article  PubMed  Google Scholar 

  41. Riegner G, Posey G, Oliva V, Jung Y, Mobley W, Zeidan F. Disentangling self from pain: mindfulness meditation-induced pain relief is driven by thalamic-default mode network decoupling. Pain. 2023;164:280–91.

  42. Creswell JD, Way BM, Eisenberger NI, Lieberman MD. Neural correlates of dispositional mindfulness during affect labeling. Psychosom Med. 2007;69:560–5.

    Article  PubMed  Google Scholar 

  43. Farb NA, Segal ZV, Mayberg H, Bean J, McKeon D, Fatima Z, et al. Attending to the present: mindfulness meditation reveals distinct neural modes of self-reference. Soc Cogn Affect Neurosci. 2007;2:313–22.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zeidan F, Salomons T, Farris SR, Emerson NM, Adler-Neal A, Jung Y, et al. Neural mechanisms supporting the relationship between dispositional mindfulness and pain. Pain. 2018;159:2477–85.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Berna C, Leknes S, Ahmad AH, Mhuircheartaigh RN, Goodwin GM, Tracey I. Opioid-independent and opioid-mediated modes of pain modulation. J Neurosci. 2018;38:9047–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Garland EL, Hanley AW, Nakamura Y, Barrett JW, Baker AK, Reese SE, et al. Mindfulness-oriented recovery enhancement vs supportive group therapy for co-occurring opioid misuse and chronic pain in primary care: a randomized clinical trial. JAMA Intern Med. 2022;182:407–17.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Morone NE, Greco CM, Weiner DK. Mindfulness meditation for the treatment of chronic low back pain in older adults: a randomized controlled pilot study. Pain. 2008;134:310–19.

    Article  PubMed  Google Scholar 

  48. Seminowicz DA, Burrowes SA, Kearson A, Zhang J, Krimmel SR, Samawi L, et al. Enhanced mindfulness based stress reduction (MBSR+) in episodic migraine: a randomized clinical trial with MRI outcomes. Pain. 2020;161:1837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Garland EL, Roberts RL, Hanley AW, Zeidan F, Keefe FJ. The mindful reappraisal of pain scale (MRPS): validation of a new measure of psychological mechanisms of mindfulness-based analgesia. Mindfulness. 2023;14:192–204.

    Article  PubMed  Google Scholar 

  50. Kjaer TW, Bertelsen C, Piccini P, Brooks D, Alving J, Lou HC. Increased dopamine tone during meditation-induced change of consciousness. Cogn Brain Res. 2002;13:255–9.

    Article  CAS  Google Scholar 

  51. Jinich-Diamant A, Garland E, Baumgartner J, Gonzalez N, Riegner G, Birenbaum J, et al. Neurophysiological mechanisms supporting mindfulness meditation–based pain relief: an updated review. Curr Pain Headache Rep. 2020;24:1–10.

    Article  Google Scholar 

  52. Benedetti F, Thoen W, Blanchard C, Vighetti S, Arduino C. Pain as a reward: changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems. PAIN®. 2013;154:361–7.

    Article  PubMed  Google Scholar 

  53. Vajirā, Maha Bodhi society Calcutta. The Sutta-nipāta, one of the oldest canonical books of the Buddhists … (English translation with Pāli text). Maha Bodhi society: Sarnath, U.P.; 1941.

  54. Adler A, Wells R, Stagnaro E, Barber L, Porter A, Garcia K, et al. Mindfulness meditation-induced pain relief does not require endogenous opioidergic systems. J Pain. 2016;17:S112.

  55. Gard T, Holzel BK, Sack AT, Hempel H, Vaitl D, Ott U. Pain attenuation through mindfulness is associated with decreased cognitive control and increased sensory processing in the brain. Cereb Cortex. 2011;191:36–43.

    Google Scholar 

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Funding

This work was supported by the National Center for Complementary and Integrative Health (Zeidan R21-AT010352, R01-AT009693, R00-AT008238) and the UC San Diego Denny T. Sanford Institute for Empathy and Compassion.

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  1. These authors contributed equally: Lora Khatib, Jon G. Dean, Valeria Oliva, Gabriel Riegner.

Authors and Affiliations

  1. Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA

    Lora Khatib, Jon G. Dean, Valeria Oliva, Gabriel Riegner, Nailea E. Gonzalez, Julia Birenbaum, Gael F. Cruanes, Jennifer Miller, Marta Patterson, Hyun-Chung Kim, Krishnan Chakravarthy & Fadel Zeidan

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Contributions

Concept and Design: F.Z. Acquisition of Data: LK, NEG, JGD, GR, JB, VO, GC, KC, JM, MP, H-CK. Statistical Analysis, Interpretation of Data, and Drafting of the Manuscript: LK, JGD, FZ. Critical Revision of the Manuscript: LK, JGD, FZ. Supervision: FZ.

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Correspondence to Fadel Zeidan.

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Khatib, L., Dean, J.G., Oliva, V. et al. The role of endogenous opioids in mindfulness and sham mindfulness-meditation for the direct alleviation of evoked chronic low back pain: a randomized clinical trial. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01766-2

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