mindfulness meditation–based pain relief: a mechanistic ......mindfulness meditation–based pain...

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Advances in Meditation Research

Mindfulness meditation–based pain relief: a mechanisticaccount

Fadel Zeidan1 and David R. Vago2

1Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, North Carolina.2Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Address for correspondence: Fadel Zeidan, Department of Neurobiology and Anatomy, Wake Forest University School ofMedicine, 1 Medical Center Boulevard, Winston-Salem, NC 27157. [email protected]

Pain is a multidimensional experience that involves interacting sensory, cognitive, and affective factors, renderingthe treatment of chronic pain challenging and financially burdensome. Further, the widespread use of opioids totreat chronic pain has led to an opioid epidemic characterized by exponential growth in opioid misuse and addiction.The staggering statistics related to opioid use highlight the importance of developing, testing, and validating fast-acting nonpharmacological approaches to treat pain. Mindfulness meditation is a technique that has been foundto significantly reduce pain in experimental and clinical settings. The present review delineates findings fromrecent studies demonstrating that mindfulness meditation significantly attenuates pain through multiple, uniquemechanisms—an important consideration for the millions of chronic pain patients seeking narcotic-free, self-facilitated pain therapy.

Keywords: mindfulness meditation; pain; fMRI; placebo; opioid

Introduction

The construction and modulation of pain are medi-ated by sensory, cognitive, and affective factors, ren-dering the treatment of chronic pain difficult andoften a financial burden. Chronic pain affects over100 million Americans and 1.5 billion people world-wide and costs the United States approximately$635 billion per year in medical expenses and lostwork productivity.1 Furthermore, the pervasive-ness and burden of chronic pain have dramati-cally increased Medicare expenditures for steroidinjections (over 629%) and opioid treatments (over423%).2 The widespread use of opioids to allevi-ate chronic pain has led to an opioid epidemic3

characterized by an exponential rise in opioid mis-use and addiction.4,5 The importance of address-ing concerns related to these staggering statisticsis reflected in new far-reaching policy changes,such as the recommendations from the Centersfor Disease Control and Prevention to develop andemploy fast-acting nonpharmacological approachesto treat chronic pain.6–8 We postulate that mindful-

ness meditation could be such a suitable narcotic-free pain therapy for a number of reasons: first,mindfulness-based meditation has repeatedly beenfound to significantly reduce chronic pain sympto-mologies;9–14 second, mindfulness meditationattenuates pain through multiple unique psycho-logical and neural processes;15–22 and further, ithas recently been demonstrated that mindfulnessmeditation is more effective in reducing pain thanplacebo23 and does not engage endogenously drivenopioidergic systems to reduce pain.20 However, alack of mechanistic classification and reproducibil-ity has reduced the clinical acceptance of medita-tion to treat pain. While there are a wide variety ofmeditation traditions and techniques, the presentreview article will focus on delineating the analgesicmechanisms supporting mindfulness meditation inparticular and take into consideration varying levelsof meditative expertise and the utility of employingrobust control/comparison conditions to better dis-entangle the specific mechanisms underlying mind-fulness meditation.

doi: 10.1111/nyas.13153

114 Ann. N.Y. Acad. Sci. 1373 (2016) 114–127 C© 2016 New York Academy of Sciences.

Zeidan & Vago Mechanisms supporting mindfulness-based analgesia

What is mindfulness meditation?

Mindfulness meditation is a fairly loose term thatapplies to many meditation practices, which havebeen found to improve a wide spectrum of clini-cally relevant cognitive and health outcomes.24–27

In patients, training in mindfulness improves self-reports of anxiety,28–31 depression,10,32–36 stress,37–39

and cognition.40–46 Mindfulness-related healthbenefits are associated with enhancements in mech-anisms supporting cognitive control, emotion reg-ulation, positive mood, and acceptance.47

Mindfulness has been described as a “non-elaborative, non-judgmental awareness” of thepresent-moment experience.9,41 However, one doesnot need to be practicing, or even be trained in,meditation to be mindful. Varying degrees of traitmindfulness exist in the general population, outsideof any formal training.48–50 Mindfulness can alsobe developed with mental training routines, such asmeditation, and there are a variety of different prac-tices that are subsumed under the general rubric ofmindfulness meditation. Thus, it is critical that thespecifics of the practice being taught or employedbe recognized. Here, we will focus on two rathercoarse categories of mindfulness practice, namely,focused attention (samatha in the Pali language)and open monitoring (Pali: vipassana),51 both ofwhich are centered on developing a number of dis-tinct cognitive skills.

During focused attention, or samatha,52 the prac-titioner is taught to develop cognitive control andattentional stability by training to sustain focus onthe moment-to-moment quality and characteris-tics of sensory, emotional, and cognitive events. Inbrief, samatha involves directing one’s attention tothe dynamic nature of the chosen object of medi-tation, most often the sensations of breath or body.When attention drifts from the object of focus, forexample, to a distracting sensory event, the prac-titioner is taught to acknowledge the event anddisengage by returning their attention back to themeditative object (e.g., the breath). Often, samathais taught as a series of distinct practices increas-ing in complexity (e.g., mindfulness of breath,emotions, and thoughts). While samatha practicesaim primarily at gaining mental control and sta-bilization of attention, they naturally lead, in asomewhat ambiguous way, to the traits associatedwith open-monitoring meditation. As a develop-mental derivative of focused-attention practice, the

mindfulness practitioner almost naturally transi-tions into an open-monitoring mental stance, alsoknown as vipassana. It is believed that extensivetraining in samatha is required before the open-monitoring aligned cognitive stance develops nat-urally. Whereas samatha often entails focus on asingle, dynamic, meditative object, open-moni-toring practices are more inclusive of perceivedthoughts and emotions. When applied to the fullextent, these practices are associated with a nondi-rected acknowledgment of any sensory, emotional,or cognitive event that arises in the mind. Whilepracticing open monitoring, the practitioner is saidto experience the current event without evalua-tion. To this extent, mindfulness meditation hasbeen described as a state of nonappraisal and/ora nonelaborative mental stance.51

Mindfulness and pain

For thousands of years, Buddhist monks havepostulated that the practice of mindfulness medita-tion can significantly alter the subjective experienceof pain. For instance, the ancient Buddhist text, theSallatha Sutta (The Arrow), states that meditationpractitioners have the unique ability to fully experi-ence the sensory aspect of pain (first arrow) but to“let go” of the evaluation (second arrow) of pain.However, only recently have scientists examined themechanisms underlying mindfulness meditation–induced pain relief and health improvements. In1980, Nepalese porters were found to report signif-icantly higher pain thresholds in response to pain-evoking electrical stimulation when compared to awell-matched control group.53 While the authorsattributed these effects to religious practices (pre-sumably meditation), it was not clear, at the time,if meditation practice directly produced analge-sia. There has recently been a significant increasein studies demonstrating that mindfulness med-itation reduces pain reports across a spectrumof chronic pain conditions.54–66 Furthermore, theadvent of neuroimaging methodologies has pro-vided cognitive scientists the means to identify thespecific neural mechanisms supporting mindfulnessmeditation–based analgesia.

Mindfulness meditation improves chronicpain symptomology

Mindfulness meditation–based interventions impr-ove pain symptomology across a wide spectrum

115Ann. N.Y. Acad. Sci. 1373 (2016) 114–127 C© 2016 New York Academy of Sciences.

Mechanisms supporting mindfulness-based analgesia Zeidan & Vago

of pain-related disorders, including fibromyal-gia,14,67 migraine,68 chronic pelvic pain,61 irritablebowel syndrome,12,13 and other conditions.69 Giventhat chronic low back pain is the most commonclinical pain condition70 and the leading cause ofdisability in the United States, it is imperative tobetter determine if and how mindfulness medi-tation training affects chronic low back pain. The8-week mindfulness-based stress reduction (MBSR)program9 is one the most studied and validatedapproaches for the treatment of chronic low backpain. In a seminal study, Kabat-Zinn et al. revealedthat chronic pain patients reported improvementsin pain symptomology and quality of life aftercompleting the MBSR program9 and improvementswere sustained after a 3-year follow-up.10 The workby Kabat-Zinn spawned a burgeoning of researchinitiatives focusing on mindfulness meditation,including a number of more recent investigationsthat have employed robust, carefully controlledexperimental designs to examine the effectivenessof mindfulness meditation interventions on chronicpain. In an elegant study, Cherkin et al.71 comparedthe effects of 8 weeks of MBSR to an 8-weekcognitive behavioral therapy (CBT) interventionand usual care across a number of chronic low backpain outcomes. The MBSR and CBT programs werefound to be significantly more effective at reducingpain intensity and reports of pain being bother-some when compared to usual care after 8, 26, and52 weeks.71 While there were no significant dif-ferences between the CBT and MBSR programs inpain-related outcomes, these findings demonstratethat mindfulness-based improvements in chronicpain could be enhanced across time. In anotherrecent study, Morone et al.55 found that an 8-weekMBSR program significantly improved numericalpain scale ratings and pain-symptom severity inolder adults (i.e., older than 65 years of age) suffer-ing from chronic low back pain when compared toa “very active” pain-related health education group.Taken together, these findings demonstrate thatrelatively brief bouts of mindfulness meditationtraining can significantly attenuate chronic lowback pain symptomology. However, the specificanalgesic neural mechanisms demonstrating howmindfulness meditation interventions producechronic pain relief have yet to determined, which isa critical step in fostering the clinical validity of thisancient technique.

The construction and modulation of pain:a brief neurophysiological synopsis

Pain is a complex and subjective conscious expe-rience constructed and modulated by sensory,cognitive, and affective factors, including mood,psychological disposition, meaning-related cogni-tions (e.g., suffering), learning, desires, and pre-paincognitive states (e.g., expectations, anxiety) to pro-vide a continually changing experience. Feedbackconnections between low-level afferent and higher-order neural processes foster the cultivation of adistributed, multidimensional network associatedwith the subjective experience of pain. Nociceptivesensory events are first registered by peripheralprimary afferents (first pain, A-delta fibers; secondpain, C fibers) at the site of injury/tissue damage,which then relay this nociceptive information tothe dorsal horn of the spinal cord. From the spinalcord, nociceptive information ascends contralateralto the site of pain to the brain, largely through thespinothalamic pathway. Nociceptive input is sub-sequently processed through feedback connectionsbetween lower-level sensory regions, including theparabrachial nucleus, periaqueductal gray matter(PAG), thalamus, and primary somatosensory (SI)and secondary somatosensory (SII) cortices.72–78

Ascending nociceptive information is then trans-mitted to the posterior and anterior insular corticeswhere it is fine-tuned to foster the subsequentevaluation of pain.79,80 The contextual meaning ofpain is then facilitated through activation of higher-order brain regions, including the dorsal anteriorcingulate cortex (dACC) and prefrontal cortex(PFC).80–82 Yet, the subjective experience of painremains to be highly influenced by the contextin which it occurs. That is, previous experiences,expectations, mood, conditioning, desires, sensiti-zation/habituation, and other cognitive factors candramatically amplify and/or attenuate pain.78,83–87

Nonpharmacological-based pain manipulationsattenuate the subjective experience of pain througha common final pathway, including overlappingendogenously driven and neural systems. While thecognitive modulation of pain is mediated through ahost of endogenous modulatory systems, includingcannabinoid, serotonergic, dopaminergic, chole-cystokinin, adrenergic, and other neurochemicalsystems (i.e., vasopressin), the endogenous opioi-dergic system is the most studied (and thus, most



understood) pain modulatory system.88 Endoge-nous opioidergic mechanisms have been repeat-edly demonstrated to mediate analgesia producedby placebo,89–93 conditioned pain modulation,94

acupuncture,95 hypnosis,96 and attentionalcontrol.97 Pain relief produced by these cognitivetechniques are associated with significant reduc-tions in pain-related brain activation (i.e., SI,SII, posterior insula, parietal operculum) andactivation in higher-order brain regions, such asthe ACC, PFC, and insula.86,89,98–110 Importantly,the PFC, insula, and ACC contain high concentra-tions of opioid receptors and are associated withproducing analgesia through descending inhibitorysystems.105,111–115 The ACC and PFC project to thePAG,116 a structure that can be directly activatedby opioids. The PAG projects to the rostral ventralmedulla,117–119 which, in turn, projects to the spinaldorsal horn and can inhibit nociceptive processingthrough multiple neurotransmitter systems.120

Brain mechanisms supportingthe modulation of pain by long-termmeditators

A large proportion of mindfulness meditation–based experimental pain research has focused onexamining the effects of meditation practice rang-ing from 8 weeks to multiple decades. In one of thefirst mindfulness meditation–focused experimentalpain studies, Grant and Rainville121 found that long-term Zen meditation practitioners required signifi-cantly higher levels of noxious thermal stimulationto report paralleling levels of pain as age-matchedcontrols. In their follow-up study with an overlap-ping sample, the authors found that, in the pres-ence of noxious thermal stimulation, long-term Zenpractitioners showed significant activation of sen-sory processing–related brain regions (thalamus,insula) and reduced activation in brain areas thatprocess the evaluation of pain (medial PFC, mPFC;orbitofrontal cortex, OFC). There was also a signifi-cant relationship between greater deactivation of themPFC/OFC, meditative experience, and lower painreports.18 Remarkably, these findings were exhibitedduring a nonmeditative cognitive state, suggestingthat long-term meditation training produces stabi-lized changes in the subjective evaluation of pain.

In addition, Lutz et al.19 examined the psy-chophysical and neural effects of meditation across14 long-term mindfulness meditation practition-

ers (approximately 10,000 h of formal meditationpractice in the Nyingma and Kagyu traditions ofTibetan Buddhism) during noxious heat stimu-lation compared to 14 non-meditating controls.The control group was provided with guidelines topractice mindfulness meditation and instructed topractice at home for 30 min/day for 1 week. Sur-prisingly, there was no difference between long-term meditators and the novice meditation groupon pain intensity ratings during samatha prac-tice. Not surprisingly, open-monitoring meditationproduced significant reductions in pain unpleas-antness in the expert meditation group when com-pared to the controls.19 This form of meditationwas associated with reduced anticipatory (beforethe painful heat stimulus) activation in the anteriorinsula. Further, the reduced baseline activation inleft anterior insula correlated with lifetime medita-tion experience. These findings and others16 indi-cate that reducing expectations of impending painis at least one process/mechanism by which mind-fulness meditation reduces pain.

In a study by Gard et al.,17 the neural mecha-nisms supporting mindfulness meditation–basedanalgesia were examined in 17 long-term vipas-sana practitioners (mean meditation practiceexperience = 5979 h) in response to noxiouselectrical stimulation compared to 17 age-, gender-,and education-matched nonmeditating controls.Similar to other studies,16,19,122 the authors didnot find a significant difference between themeditation and control groups in pain intensityratings, but did find a significant reduction in painunpleasantness ratings compared to the controlgroup during the mediation state in the presenceof noxious stimulation.17 Greater activation of thecontralateral SII/posterior insula was associatedwith meditation-induced pain unpleasantnessratings. The authors also found greater rostral ACC(rACC) and ventromedial PFC (vmPFC) activa-tion during the pre-stimulus anticipatory phase,suggesting that cognitive control mechanisms wereat play. However, meditation-induced analgesiawas directly associated with greater deactivation ofthe PFC and increased activation of the posteriorinsula, which is consistent with the abovemen-tioned work by Grant and Rainville.18 Takentogether, these findings are important because theydemonstrate that the neural mechanisms involvedin mindfulness-based pain relief are consistent with



the postulated psychological expression/experienceof mindfulness (i.e., greater sensory processing andparallel reductions in pain appraisal).

These findings have advanced our knowledgeof the mechanisms supporting the stabilized psy-chological and neural changes associated with long-term meditation practice. Yet, the utility of med-itation for treating pain remains limited becauseof the assumption that the benefits of meditationrequire lengthy training regimens.15,27 Specifically,extensive class time requirements123 and overalllength of meditation training regimens have beencited as leading barriers to the clinical utility ofmeditation interventions.124 Furthermore, theaforementioned studies employed cross-sectionaland/or case–control designs, consequently lim-iting their generalizability because of the widespectrum of potential between-group differences(e.g., demographics, demand characteristics, andmeditative tradition).15 Thus, random assignmentand longitudinal designs are encouraged formeditation-focused studies.27 In light of these find-ings, we postulate that if the benefits of meditationcan be elicited by brief mindfulness-based mentaltraining regimens, then meditation may be morefeasible to apply in clinical settings.

Mindfulness meditation after brief trainingreduces pain through unique mechanisms

Recent studies from our laboratory have focusedon disentangling the specific analgesic, behavioral,neural, and pharmacologic mechanisms involved inmindfulness meditation–related pain relief. In 2011,we examined the effects of mindfulness meditationin 15 healthy pain-free subjects after participation ina brief (four sessions, 20 min/session) mindfulnessmeditation–based intervention on experimentallyinduced (ten 12-s plateaus of 49 °C) pain, usingarterial spin labeling (ASL) functional magneticresonance imaging (fMRI). ASL is a neuroimagingtechnique that provides a direct quantifiablemeasurement of global cerebral blood flow, animportant consideration for breathing-focusedcognitive practices, such as meditation.21 Duringmeditation training, subjects were instructed toclose their eyes, sit with a straight posture and focuson the breath sensations, acknowledge distractingthoughts and feelings, and to simply let go of arisingsensory events without judgment. Participants weretaught that perceived sensory and affective events

are momentary and fleeting and do not requirefurther evaluation. In the first two meditationtraining sessions, subjects were instructed to focuson the breath sensations occurring at the tip of thenose and full flow of the breath. Meditation, afterthe four-session intervention, during noxious heatproduced a mean 40% reduction in pain intensityand 57% reduction in pain unpleasantness ratings.Greater activation of the subgenual ACC (sgACC),OFC, and right anterior insula (Fig. 1) was associ-ated with mindfulness meditation–based analgesia.The sgACC is critically involved in the cognitiveand affective control of pain.83,86,99,125,126 The OFChas been implicated in altering the contextualevaluation of arising sensory events,127–130 and theright anterior insula is associated with the modula-tion of afferent nociceptive processing74,75,80,100,131

and processing interoceptive awareness.132–134 Wealso found that mindfulness meditation–basedpain relief was associated with greater bilateralthalamic deactivation (Fig. 1).21 Thus, meditationmay reduce pain by fine-tuning the amplificationof nociceptive sensory events through top-downcontrol processes,15,21,23 potentially reflected by thesignificant attenuation of SI activation correspond-ing to the stimulation site when subjects meditatedduring noxious heat when compared to rest (rightleg).21 We postulated that mindfulness meditationattenuates pain through engagement of top-down(OFC to thalamus) inhibition of ascending noci-ceptive information.15,20,21,23 Thus, the cognitivestate of mindfulness meditation–based analgesiadoes not reduce pain through one avenue but rathermultiple, unique neural mechanisms. Althoughthis study employed a longitudinal design, a controlgroup was not included. However, our follow-upstudies addressed this caveat.20,23

Does mindfulness meditation engagemechanisms consistent with placeboanalgesia?

While mindfulness meditation practice can improvehealth and well-being, the active mechanisms sup-porting mindfulness meditation have yet to befully characterized. Importantly, a wide rangeof nonspecific placebo-related effects are likelyinvolved during meditation training. Here, wedefine the placebo response as benefits or effectsdriven by nonspecific and/or inert dimensions ofa drug, intervention, or manipulation. Nonspecific



Figure 1. Mindfulness meditation–based pain relief is associated with multiple brain mechanisms. Regression analyses corre-sponding to those in Zeidan et al.21 revealed that reductions in mindfulness meditation–induced pain intensity were associated withgreater activation (depicted in red) in the right anterior insula and rostral aspects of the anterior cingulate cortex (ACC). Greaterreductions in pain unpleasantness ratings were associated with greater activation of the orbitofrontal cortex (OFC) and thalamicdeactivation (depicted in blue).

and potentially confounding variables, such asconditioning effects, psychosocial contexts, facili-tator attention, intervention setting, body posture,and/or demand characteristics associated with thebelief that one is practicing meditation,15,27,135

could mediate mindfulness meditation–relatedhealth improvements.136,137 Randomized, placebo-controlled studies are the gold-standard approachto identify the effectiveness and specific mecha-nisms supporting the modulation of pain by mind-fulness meditation. Yet, placebo-controlled medita-tion studies have been limited, which is problematicwhen considering that meditation is arguablyhighly susceptible to placebo-type effects.

Some recent studies have successfully disentan-gled the processes by which meditation affectshealth. For example, Creswell et al.138 examinedthe behavioral and inflammatory stress markers(i.e., interleukin-6 (IL-6)) and neural mechanismsrelated to participating in an intensive 3-day mind-fulness meditation intervention compared to a3-day health enhancement relaxation program inunemployed and clinically stressed adults. Theresearchers matched all aspects of the relaxationprogram to the meditation intervention, includingsitting in silence, meals, stretching exercises, slowwalking, facilitator interviews, and even the locationof the intervention. Both groups reported significantdifferences in perceived stress. However, increaseswere shown in pre- to post-meditation interven-

tion functional neural connectivity between a cen-tral node of the default fault mode network (i.e., pos-terior cingulate cortex (PCC) and the dorsolateralPFC (dlPFC)), a brain region implicated in cognitiveand affective control. Furthermore, the dlPFC–PCCconnectivity mediated reductions in circulating IL-6from baseline to the 4-month follow-up. In contrast,the relaxation intervention group exhibited mildincreases in IL-6 after the intervention. These find-ings provide supplementary evidence that mind-fulness meditation employs unique mechanisms toimprove health in clinically relevant populations.

Another research group developed an activecomparison intervention, referred to as a healthenhancement program (HEP), to specifically iso-late and control for the effects of MBSR.139–141 TheHEP was postulated to control for facilitator alle-giance, time spent providing instruction/therapy,social support, and other components related toparticipating in an MBSR program.139 Although theHEP and MBSR program were effective at reduc-ing self-reports of anxiety, distress, hostility,139 andattentional stability,140 there were no significantdifferences between groups. However, the MBSRprogram was more effective at reducing inflamma-tory responses following social stress141 and exper-imentally induced pain ratings.139 These studiesdemonstrated the unique health-promoting prop-erties supporting mindfulness-based health promo-tion. However, the question arises as to whether



Figure 2. The main effects of mindfulness meditation and sham mindfulness meditation involve similar neural processes.Mindfulness meditation and sham mindfulness meditation produced activation (red) in the bilateral putamen and primarysomatosensory cortex (SI) corresponding to the nose/face regions and deactivation (blue) of the medial prefrontal cortex (mPFC)and precuneous/poster cingulate cortex (PCC). Mindfulness meditation also activated the right inferior frontal gyrus and produceddeactivation of the bilateral thalamus. Conjunction analyses revealed significant overlapping activation in the bilateral putamen,SI representation of the nose/face, and deactivation of the PCC and mPFC.

it is possible that the benefits of meditation maysimply be related to the belief that one is practicingmindfulness meditation.

A recent study23 examined whether mindful-ness meditation–based pain relief engages neuralmechanisms that are distinct from placebo anal-gesia and sham mindfulness meditation–relatedanalgesia. Similar pain-evoking thermal stimula-tion paradigms and neuroimaging methods (ASLMRI) were employed as described previously.21

Seventy-five healthy, pain-free subjects were ran-domly assigned to one of four 4-session (20 min/session) regimens: (1) a brief mindfulness med-itation intervention similar to an interventiondescribed previously,21,31,36,46,142 (2) placebo con-ditioning, (3) sham mindfulness meditation, and(4) a book-listening intervention. Participants inthe placebo-conditioning group were led to believethat the effects of an experimental form of lido-caine was being tested, in which the analgesic effectsof the cream (placebo cream was petroleum jelly)progressively increase as a function of repeatedapplications. To enhance placebo conditioning, thestimulus temperatures delivered to the treated skinwere covertly reduced, from 49 °C, in a progressive

fashion across sessions (placebo conditioning ses-sion 1: 48 °C; sessions 2 and 3: 47 °C; session 4:46.5 °C). The 49 °C stimulus was administered afterapplying/removing the placebo cream in the postin-tervention MRI session to measure the efficacy of theplacebo conditioning regimen. The sham mindful-ness meditation intervention was designed so thatthe only difference in training between the mindful-ness and sham mindfulness meditation groups wasthe explicit mindfulness-based instructions (e.g.,nonjudgmental attention to the breath) given to themindfulness meditation group. Subjects were firstinformed that they were randomly assigned to themindfulness meditation intervention. Across four20-min sessions, participants were trained to takedeep breaths “as we sit here in mindfulness medi-tation.” The control group listened to the NaturalHistory of Selborne143 across four sessions.

All cognitive manipulations (mindfulness medi-tation, placebo cream, sham mindfulness medita-tion) reduced pain intensity and unpleasantnessratings compared to the control group. Impor-tantly, mindfulness meditation was significantlymore effective at reducing pain than both placebogroups. Mindfulness meditation–based pain relief



Figure 3. Psychophysical pain intensity (left graph) and unpleasantness (right graph) ratings (95% confidence intervals).20

Meditation during saline (meditation + saline) infusion significantly (P < 0.001) reduced pain intensity and unpleasantnessratings compared with rest and the control and saline (control + saline) group. Naloxone did not reverse meditation-induced painrelief. Meditation during naloxone administration (meditation + naloxone) significantly (P < 0.001) reduced pain intensity andunpleasantness ratings compared with rest, the control + saline group, and the control and naloxone (control + naloxone) groups.There were also no significant differences in pain intensity or unpleasantness ratings between the meditation + saline and themeditation + naloxone groups (P > 0.69).

was associated with similar brain activation asin our previous neuroimaging study,21 includinggreater activation of the OFC, pregenual ACC,and right anterior insula. Placebo-cream analgesiawas associated with significant reductions in pain-related brain activation (posterior insula/parietaloperculum; secondary somatosensory cortices) andproduced greater activation in the thalamus andPAG compared to mindfulness meditation. Inter-estingly, the main effects of mindfulness medita-tion and sham mindfulness meditation significantlyoverlapped in activation of the bilateral putamen, SIcorresponding to the nose/mouth, and the dACC,suggesting that the two breathing-focused practicesengage similar mechanisms (Fig. 2). However, thetwo techniques were associated with significantlydistinct neural processes when the analyses werefocused on the pain-related MRI series. In con-trast to mindfulness meditation, sham mindful-ness meditation produced greater activation in thethalamus and deactivation of the rostral ACC.Importantly, sham mindfulness meditation–relatedanalgesia was associated with greater reductions inrespiration rate, demonstrating a mechanistic dif-ference between sham and mindfulness meditation.That is, mindfulness meditation–related pain reliefwas associated with greater executive-level mod-ulation of pain and, in contrast, sham mindful-ness meditation–induced analgesia was driven bybottom-up processes consistent with placebo andrelaxation.144

While the endogenous pain modulatory systemssupporting mindfulness-based analgesia remainunknown, it is well established that the cognitivemodulation of pain, including manipulations suchas placebo,89,91–93,105,145 conditioned pain modu-lation,94 and attentional control,97 is partiallydependent on descending pain control systems98,146

and can be reversed by the opioid antagonist nalo-xone.90,91,97,147 Interestingly, meditation reducespain by engaging brain regions (sgACC, OFC,anterior insula) that contain high concentra-tions of opioid receptors.92,111,113,148 On the otherhand, mindfulness meditation also reduces acti-vation in the PAG, a brain region involvedin facilitating opioid-mediated descending paininhibition.72,149 Thus, a recent double-blind psycho-physical study tested whether mindfulness medi-tation–based analgesia was mediated by endogenousopioids; 78 healthy pain-free subjects were random-ized to one of four 4-session intervention groups(meditation + naloxone, book-listening control +naloxone, meditation + saline, book-listening con-trol + saline) to determine if intravenous admin-istration of high doses of naloxone would reversemeditation-induced analgesia. Surprisingly, it wasfound that, independent of naloxone or placebo-saline administration, meditation significantlyreduced pain intensity and unpleasantness ratingscompared to rest and the control groups (Fig. 3).20

These findings provide supplementary evidence thatmindfulness meditation engages mechanisms that



are distinct from placebo to reduce pain and areof critical importance to the millions of chronic-pain patients seeking a fast-acting nonopioid paintherapy. Specifically, it was proposed that thecombination of mindfulness-based and pharmaco-logic/nonpharmacologic analgesic strategies may beparticularly effective in the treatment of pain.

Conclusion

Mindfulness meditation engages multiple uniquebrain mechanisms that attenuate the subjectiveexperience of pain. Yet, analgesic mechanisms sup-porting mindfulness-based meditation change asa function of increasing meditative experience/training. While meditation after brief training(less than 1 week) produces significant redu-ctions in pain intensity and unpleasantnessratings,20,21,23,122,142 long-term meditation does notproduce changes/differences in pain intensity butrather influences the unpleasantness dimension ofself-reported pain.17,121,122 This proposed change inthe subjective experience is likely attributable toa shift in approach to meditating in the contextof incoming sensory information between noviceand adept practitioners. For instance, a shift inmeta-awareness has been proposed,45 in whichadept meditators can engage an invasive sensa-tion (e.g., pain) without appraising/evaluating theevent. It remains unclear how this shift changesas a function of greater practice.51,52,150 Never-theless, it is not surprising that a decouplingbetween sensory and appraisal-related brain regionsis exhibited in adept meditators in the presence ofnoxious stimulation.17,18 In contrast, novice med-itators engage more effortful reappraisal processesto reduce pain and adept meditators employ non-appraisal mechanisms.

We propose that, at the early stages of training,mindfulness meditation alters the evaluation andmeaning of pain as a function of self-referentialprocessing. Subject testimonials from our previ-ous studies20,21,23,142 provide supplementary sup-port for this hypothesis. Study subjects routinelystated that the experience of noxious heat stim-ulation during meditation was “shorter,” “softer,”and accompanied with “less dwelling” and a greaterability to “fully embrace the feeling of pain,” butto simply “let go” of the appraisal of what thepain meant to them. These reports are remark-ably consistent with the mindfulness principles that

were instilled during their meditation training. Neu-roimaging data provide supplementary support forthese experiences. Novice meditators recruit higher-order brain regions (OFC, sgACC, anterior insula)to downregulate ascending nociceptive input at thelevel of the thalamus through shifts in executiveattention.21,23 Thus, meditation after brief mentaltraining affects sensory and affective pain-relatedresponses. The comprehensive modulation of boththe intensity- and unpleasantness-related dimen-sions of pain is hypothetically facilitated throughchanges in executive attention. Activation of theOFC may facilitate inhibitory connections of thethalamic reticular nuclei to further reduce the elab-oration of nociceptive information throughout thecortex (evidenced by reductions in thalamic, PAG,and SI activation).21,23 Thus, brief mental training inmindfulness meditation engages cortico-thalamo–cortical interactions to reduce pain through mecha-nisms such as inhibitory control45 or reappraisal (or“re-perceiving”151) to essentially “close the gate” onascending nociceptive information. In contrast, theneural mechanisms involved in long-term medita-tion practice are associated with significantly greateractivation in somatosensory regions and deactiva-tion of appraisal-related brain regions (vmPFC).17,18

The decoupling between the sensory experience andthe meaning and/or contextualization of what thepain means to the self, in long-term meditationpractitioners, provides evidence that the analgesiceffects of meditation can be developed and enhancedthrough greater practice, a critical consideration forthose seeking long-lasting narcotic-free pain relief.

When taking into consideration the currentchronic pain1 and opioid epidemic,152,153 the use ofmind–body approaches, such as mindfulness med-itation, may prove to be an important resource toteach patients to self-regulate the experience of paindirectly with a present-centered and acceptance-based focus. Converging lines of evidence demon-strate that mindfulness meditation significantlyattenuates pain across clinical and experimentalsettings. In contrast to other health outcomes, thehealth-promoting effects of meditation are mostpronounced for pain and pain-related comorbidi-ties, including opioid addiction and misuse,154–157

stress,37,138 depression,158–160 and anxiety.31,161,162

Some recent studies of fibromyalgia22 and chroniclow back pain54 patients who received mindfulnesstraining also see a similar decoupling of sensory



and affective pain, such that pain intensity orfrequency does not necessarily decrease, but copingwith the pain does improve. Furthermore, acrossalmost all mindfulness/pain-focused experiments,the unpleasantness dimension of pain was sig-nificantly more attenuated with respect to painintensity,16–21,23,121,122 which is a critically importanteffect when considering the use of meditation forclinical pain. For instance, the experience of chronicpain is dramatically influenced by the context inwhich it occurs. One example of this comes fromstudies assessing pain in patients and in womengiving birth.163 The pain of labor was rated assignificantly higher on sensory aspects compared tothe affective dimension. In contrast, cancer pain wasrated significantly higher on pain unpleasantnessthan pain intensity.164 The suggestion here is thatthe contextual evaluation of welcoming a new babyinto the world when compared to facing one’s owndeath has profound implications for what mighthave otherwise been very similar experiences. Wesuggest that mindfulness, in a similar, albeit lessprofound, manner as giving birth or dying, alsoalters the meaning, interpretation, and appraisalof nociceptive information, an important consid-eration for producing stabilized and long-lastingimprovements in chronic pain symptomology, andcan potentially serve as a mechanism to bufferagainst the chronification of pain.

Conflicts of interest

The authors declare no conflicts of interest.

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