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Mindfulness Meditation Modulates Pain Through Endogenous Opioids

  • Haggai Sharon
    Correspondence
    Requests for reprints should be addressed to Haggai Sharon, MD, Functional Brain Center, Wohl Institute for Advanced Imaging, Sourasky Medical Center, 6 Wiezman St., Tel Aviv, Israel.
    Affiliations
    Functional Brain Center, Wohl Institute for Advanced Imaging, Sourasky Medical Center, Tel Aviv, Israel

    The Institute for Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Sourasky Medical Center, Tel Aviv, Israel
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Adi Maron-Katz
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Functional Brain Center, Wohl Institute for Advanced Imaging, Sourasky Medical Center, Tel Aviv, Israel
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Eti Ben Simon
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Functional Brain Center, Wohl Institute for Advanced Imaging, Sourasky Medical Center, Tel Aviv, Israel
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  • Yuval Flusser
    Affiliations
    Functional Brain Center, Wohl Institute for Advanced Imaging, Sourasky Medical Center, Tel Aviv, Israel
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  • Talma Hendler
    Affiliations
    Functional Brain Center, Wohl Institute for Advanced Imaging, Sourasky Medical Center, Tel Aviv, Israel
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  • Author Footnotes
    2 These authors contributed equally to this work.
    Ricardo Tarrasch
    Footnotes
    2 These authors contributed equally to this work.
    Affiliations
    School of Education, Tel Aviv University, Israel
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  • Author Footnotes
    2 These authors contributed equally to this work.
    Silviu Brill
    Footnotes
    2 These authors contributed equally to this work.
    Affiliations
    The Institute for Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Sourasky Medical Center, Tel Aviv, Israel
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  • Author Footnotes
    1 These authors contributed equally to this work.
    2 These authors contributed equally to this work.

      Abstract

      Background

      Recent evidence supports the beneficial effects of mindfulness meditation on pain. However, the neural mechanisms underlying this effect remain poorly understood. We used an opioid blocker to examine whether mindfulness meditation-induced analgesia involves endogenous opioids.

      Methods

      Fifteen healthy experienced mindfulness meditation practitioners participated in a double-blind, randomized, placebo-controlled, crossover study. Participants rated the pain and unpleasantness of a cold stimulus prior to and after a mindfulness meditation session. Participants were then randomized to receive either intravenous naloxone or saline, after which they meditated again, and rated the same stimulus.

      Results

      A (3) × (2) repeated-measurements analysis of variance revealed a significant time effect for pain and unpleasantness scores (both P <.001) as well as a significant condition effect for pain and unpleasantness (both P <.2). Post hoc comparisons revealed that pain and unpleasantness scores were significantly reduced after natural mindfulness meditation and after placebo, but not after naloxone. Furthermore, there was a positive correlation between the pain scores following naloxone vs placebo and participants' mindfulness meditation experience.

      Conclusions

      These findings show, for the first time, that meditation involves endogenous opioid pathways, mediating its analgesic effect and growing resilient with increasing practice to external suggestion. This finding could hold promising therapeutic implications and further elucidate the fine mechanisms involved in human pain modulation.

      Keywords

      Clinical Significance
      • Meditation-induced analgesia involves endogenous opioids that mitigate its beneficial effect on pain.
      • Our results suggest that with increasing experience this process becomes unaffected by cognitive manipulation.
      • These observations support the notion that cultivating a long-term practice of meditation in chronic pain patients may have potential therapeutic effects.
      Pain is a complex and multifaceted phenomenon involving sensory, cognitive, and emotional brain processes.
      • Apkarian A.V.
      • Baliki M.N.
      • Geha P.Y.
      Towards a theory of chronic pain.
      In recent years, a growing body of research has provided support for the beneficial effects of mindfulness meditation on acute and chronic pain.
      • Reiner K.
      • Tibi L.
      • Lipsitz J.D.
      Do mindfulness-based interventions reduce pain intensity? A critical review of the literature.
      • Jensen M.P.
      • Day M.A.
      • Miro J.
      Neuromodulatory treatments for chronic pain: efficacy and mechanisms.
      Because mindfulness meditation has been shown to enhance cognitive control and improve emotion regulation,
      • Hölzel B.K.
      • Lazar S.W.
      • Gard T.
      • Schuman-Olivier Z.
      • Vago D.R.
      • Ott U.
      How does mindfulness meditation work? Proposing mechanisms of action from a conceptual and neural perspective.
      • Maron-Katz A.
      • Ben-Simon E.
      • Sharon H.
      • Gruberger M.
      • Cvetkovic D.
      A neuroscientific perspective on meditation.
      • Tang Y.Y.
      • Hölzel B.K.
      • Posner M.I.
      The neuroscience of mindfulness meditation.
      a placebo-like mechanism of top-down control involving suggestion and expectation has been proposed as enabling such meditation-induced analgesia.
      • Bushnell M.C.
      • Ceko M.
      • Low L.A.
      Cognitive and emotional control of pain and its disruption in chronic pain.
      However, the neurofunctional and neurochemical mechanisms underlying this analgesic effect remain poorly understood. By using an opioid blocker during mindfulness-meditation modulation of a painful stimulus, we aimed to examine whether mindfulness meditation-induced analgesia is mediated via endogenous opioids, and if so, whether it is susceptible to manipulation by suggestion/expectation.

      Methods

      Fifteen healthy mindfulness-meditation practitioners participated in 30 sessions of a double-blind, randomized, placebo-controlled, crossover study. All participants were recruited from the same meditation practice center in Tel Aviv and had over a year's experience of at least one hour of practice a day at least 3 times a week. All practiced sitting mindfulness meditation and referred to the type of practice that they perform as Shamatha or Vipassana meditation.
      • Maron-Katz A.
      • Ben-Simon E.
      • Sharon H.
      • Gruberger M.
      • Cvetkovic D.
      A neuroscientific perspective on meditation.
      All participants had no previous or current neurological or psychiatric disorders, and did not suffer from any chronic pain (constant or episodic syndromes). One subject was excluded from the analysis due to technical difficulties with the intravenous line; thus, the final analyses included 14 subjects. Participants were asked to rate the pain and unpleasantness of a cold stimulus (immersing their hand in icy water, 2°C-4°C, for 10 seconds) using a visual analog scale score prior to and after a normal mindfulness-meditation session (nonmanipulation condition). Participants were then randomized to receive either 0.1 mg/kg of intravenous naloxone, an opioid antagonist, or intravenous saline, after which they meditated again, and then rated the same painful stimulus. On a different date (a mean of 7 days apart), each participant underwent the same procedure in a crossover-counterbalanced design. The study was reviewed and approved by the Tel Aviv Medical Center Ethics Committee.

      Results

      A (3) × (2) repeated-measurements analysis of variance was performed separately for both pain and unpleasantness scores for the within-subjects factors of time (prior to/after meditation) and condition (no treatment, naloxone or placebo injection). Both analyses revealed a significant time effect [F(1, 13) = 19.01 for pain ratings; F(1, 13) = 22.85 for unpleasantness, both P <.001], as well as a significant condition effect [F(2, 26) = 4.62 for pain ratings; F(2, 26) = 9.01 for unpleasantness, both P <.2]. Both measurements further revealed a significant interaction between time and condition [F(2, 26) = 3.68, for pain ratings; F(2, 26) = 4.61 for unpleasantness, both P <.04]. Tukey honest significant difference post hoc comparisons revealed that pain and unpleasantness scores were significantly reduced after natural mindfulness meditation, compared with baseline (from 6.11 ± 0.46 to 4.21 ± 0.5, and from 5.8 ± 0.47 to 3.4 ± 0.44, both P <3E-5), as well as after placebo administration (from 6.14 ± 0.48 to 5 ± 0.66, and from 5.71 ± 0.48 to 4.28 ± 0.58, both P <.01), but not after naloxone administration (from 6 ± 0.47 to 5.2 ± 0.56, P = 0.1, and from 5.9 ± 0.5 to 4.78 ± 0.5, P = 0.07, respectively) (Figure, top panel).
      Figure thumbnail gr1
      Figure(Top panel) Mean pain and unpleasantness scores. Mean pain (A, left panel) and unpleasantness scores (B, right panel) following: a painful cold stimulus (baseline); natural meditation; meditation after placebo administration; and meditation after naloxone administration, respectively. Bars represent standard error. (Bottom panel) The differences in pain scores following naloxone vs placebo and participants' mindfulness meditation (MM) experience. The positive correlation of the response to intervention with years of experience suggests reduced response to placebo with increasing experience.
      To further explore the development of mindfulness-meditation analgesia, we tested the correlation between the differences in pain scores following naloxone vs placebo and participants' mindfulness-meditation experience. Interestingly, a significant correlation was found (r = 0.67, P <.01; Figure, bottom panel) suggesting reduced response to placebo with increasing experience.

      Conclusions

      In line with previous reports, we found that mindfulness meditation induces a significant analgesic effect. However, we found that this effect was reversed by the administration of an opioid antagonist, indicating the recruitment of the endogenous opioid system during meditation.
      Interestingly, in this study there was a significant correlation between the differential response to naloxone vs saline and participants' meditation experience, with saline being more likely to reverse the mindfulness meditation-induced analgesic effect in less-experienced practitioners. This sensitivity to placebo in less-experienced meditators implies the contribution of cognitive-emotional top-down mechanisms that are still susceptible to expectation. Such mechanisms do not appear to be as sensitive to manipulation in more experienced meditation practitioners. This finding supports the growing recent evidence from brain imaging studies indicating that the neural mechanisms underlying mindfulness meditation-induced analgesia are different from those that underlie placebo analgesia.
      • Zeidan F.
      • Emerson N.M.
      • Farris S.R.
      • et al.
      Mindfulness meditation-based pain relief employs different neural mechanisms than placebo and sham mindfulness meditation-induced analgesia.
      Moreover, it suggests that mindfulness meditation-induced analgesia is shaped by a dynamic neural process that evolves with time and experience — while in early stages it seems to rely mostly on mechanisms related to suggestion, it later becomes a dedicated opioid-mediated process that is less susceptible to external psychological manipulation. This observation also echoes findings of macroanatomical changes in gray matter density among long-term meditators, which also suggest a robust and ongoing modulation of brain function.
      • Hölzel B.K.
      • Lazar S.W.
      • Gard T.
      • Schuman-Olivier Z.
      • Vago D.R.
      • Ott U.
      How does mindfulness meditation work? Proposing mechanisms of action from a conceptual and neural perspective.
      • Bushnell M.C.
      • Ceko M.
      • Low L.A.
      Cognitive and emotional control of pain and its disruption in chronic pain.
      Interestingly, a recent study has also shown a similar principle for placebo — for example, in migraine patients taking placebo medications that were explicitly labeled “placebo” and experiencing significant pain relief compared with no treatment,
      • Kam-Hansen S.
      • Jakubowski M.
      • Kelley J.M.
      • et al.
      Altered placebo and drug labeling changes the outcome of episodic migraine attacks.
      suggesting that a learned association between pill taking and a beneficial effect makes the very habit of pill taking beneficial in itself over time, regardless of explicit external suggestion. Our results further support recent proposals
      • Zeidan F.
      • Grant J.A.
      • Brown C.A.
      • McHaffie J.G.
      • Coghill R.C.
      Mindfulness meditation-related pain relief: evidence for unique brain mechanisms in the regulation of pain.
      that future study of mindfulness meditation-induced analgesia should explore its temporal dynamics, as well as its delineation from other cognitive-emotional means of modulating pain in humans, by using integrated structural and functional neuroimaging techniques in meditators with varying levels of experience or in a longitudinal manner. Of note, this study included only healthy volunteers. Therefore, whether these observations remain valid in patients with acute or chronic pain, especially those with current or previous exogenous opioid exposure, remains to be explored.
      To conclude, our findings suggest that meditation physiologically involves endogenous opioid pathways, which in turn participate in mediating its analgesic effect, and which become resilient to external suggestion with increasing practice. Cultivating a robust ability to endogenously modulate pain using meditation could hold promising therapeutic implications, and further elucidate the fine mechanisms involved in human pain modulation.

      Acknowledgment

      The authors wish to thank Mr. Avy Lugassy for his support.

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