Mindfulness Training as a Tool to Combat Acute-to-Chronic Pain Transition in Predisposed Populations

Posted on by BUJPH

image of someone meditating

By Alexis Peetz Alio

Illustration by Mena Kassa

 

Abstract

The transition from acute to chronic pain involves changes in neural circuits associated with learning and emotion. This study explores the potential of mindfulness training as a preventive measure to combat the acute-to-chronic pain transition in predisposed populations. Longitudinal studies have uniquely revealed the predictive power of functional connectivity within specialized circuits that incorporate the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and anterior cingulate cortex (ACC) in the persistence of pain. Stress mechanisms driven by cortisol also play a significant role in pain perception and hypersensitization linked to chronic pain. Mindfulness training, which aims to promote non-reactive and non-judgmental awareness of the present moment, has been shown to produce promising therapeutic effects in managing chronic pain. Studies have demonstrated changes in key limbic and prefrontal regions following such practices. Meditating has also been associated with reduced pain unpleasantness, low anticipatory cortisol reactivity, and increased connectivity between emotion-regulating and sensory-related brain areas, such as the dlPFC and NAc. While mindfulness interventions have been studied extensively in the context of chronic pain management, their potential as a preventative measure remains largely unexplored. This review summarizes the therapeutic effects of mindfulness training on the neural mechanisms involved in the transition from acute to chronic pain. It aims to provide a framework to encourage future clinical trials to consider novel approaches to combat the chronic pain epidemic.

Key words: Chronic pain, Acute-to-chronic pain transition, Mindfulness, Meditation, Medial prefrontal cortex, Nucleus Accumbens, Anterior cingulate cortex, Cortisol reactivity

Conflict of Interest declaration: The author declares that they have NO affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript

 

Introduction

Chronic pain is an extremely prevalent condition among adults worldwide; however, owing to its complex nature, its underlying mechanisms are not fully understood. Pain-related disabilities can manifest in different ways. More than 8 percent of US adults suffer from chronic back pain, while tension-type headaches affect approximately 1 to 3 percent of adults on the basis of more than 15 days out of every month.1,2 Serious injuries, illness, or surgical operations can often lead to lifelong suffering, with 5 to 10 percent of patients exhibiting acute back pain progressing to a chronic state.3 The body can become hypersensitized as a result of repetitive or traumatic pain through a protective process called central sensitization. This occurs when excitability is increased or inhibitory influences are suppressed in peripheral and dorsal horn neurons through a combination of intracellular changes involving calcium concentration and NMDA receptor trafficking. These changes can become pathological as a result of transcription-related modifications when a pain-eliciting stimulus or reactive inflammation persists.4 Interestingly, it has been shown that higher-level perceptual functions and emotions associated with activity in the brain are also highly involved in modulating our experience of pain; even the chronification of pain seems to be linked to changes in mental states and neuropsychological factors, rewiring the brain to further exacerbate a person’s perception of painful and non painful stimuli.5 Patients suffering from long-term headaches, arthritis, back pain, and other related conditions have begun to turn to cognitive therapy and mindfulness-meditation-based regimens to manage their symptoms. These practices are now widely implemented in parallel with medications and lifestyle changes with extremely positive outcomes, backed by a growing pool of literature emphasizing the beneficial effects of meditation on brain regions associated with emotion, perception, learning, and addiction. Treatment options for chronic pain are still limited, however, to short-term solutions – such as pills, operations, and therapy – while actual cures are rare, unless the specific cause can be pinpointed and addressed.6 The next step would be to consider the implementation of preemptive treatments. As an alternative to symptom management, a focus on prevention might provide an effective solution to deal with the chronic pain epidemic. 

Current studies suggest that in contrast to acute pain, which occurs at the level of somatosensory pathways, persistent abnormal pain processes disproportionately engage reward evaluation and stress pathways associated with emotion and learning in the central nervous system. Inherent measurable differences in these neural circuits may represent risk factors involved in the transition from acute to chronic pain. Mindfulness meditation, which is widely studied for its profound therapeutic influence across the brain and body, targets some of these preliminary elements of chronic pain and thus may prove to be a useful clinical tool in pathologically predisposed populations.

 

Neural Mechanisms Underlying the Predictive Nature of Chronic Pain

The mPFC-NAc pathway has recently been recognized as a dominant predictor and amplifier of chronic pain. The medial prefrontal cortex (mPFC) is important for context-dependent memory formation and emotion-driven self-reflection.7,8 Various other neural systems work in conjunction with this region to invoke meta-processing of both internal and external inputs. The nucleus accumbens (NAc) is a major component of the reward system of the brain and is responsible for modulating dopamine secretion; it contains cells that bind various neurotransmitters including endogenous opiates.9 This ‘pleasure center’ of the brain evaluates a wide range of inputs to reinforce learning; in turn, the mPFC generates perceptual and emotional feedback and relays this information to memory centers to assign lingering qualities to future analogous inputs. Synchronized activity in these regions has been observed during spontaneous pain spurs in patients with chronic back pain, implying that the chronification of pain may stem from emotional or reflexive processes.7 One of the pioneering MRI experiments profiling the transition from acute to chronic pain tracked temporal changes in the brains of patients following a short-term episode of subacute back pain. This study, published by Baliki et al. (2012), was the first to reveal that subjects with greater initial mPFC-NAc functional connectivity were more likely to develop chronic symptoms. Compared to those who returned to a healthy state, subjects who fell into the ‘persisting’ group exhibited stronger functional connectivity in their initial scan, which was administered within 13 weeks of the onset of their symptoms, and in their final scan, which occurred approximately one year later. Functional imaging results from the first trial predicted the probability of self-reported pain persistence at the final visit with 83 percent accuracy. Pain persistence was also characterized by progressive decreases in gray matter density in both the NAc and insula across the 4-scan period.10 These findings have major implications for chronic pain research, establishing the first significant biomarker with high predictive power, and presenting a stronger and more up-to-date mechanistic model of its functional origins: the role of corticostriatal neurons could suggest that chronic pain is learned, and the involvement of limbic circuitry may render this type of pain more emotional.7 

This model incorporates a number of prefrontal and limbic systems, which together modulate and distort the suffering of noxious experiences. A subsequent longitudinal study conducted in 2016 by Vachon-Presseau et al. expanded upon previous results by following a similar procedure conducted over three years. Reduced amygdala volume was implicated as a risk factor, along with increased white matter volume and functional connectivity within a specialized circuit incorporating the dorsal medial PFC, NAc, and amygdala.11 The amygdala is central to the aforementioned model; it plays a role in emotion and stress, potentially amplifying the negative evaluation of pain within this circuit. Three more important limbic structures are present: the hippocampus, insula, and anterior cingulate cortex (ACC). The ACC is directly involved in pain, emotional evaluation, and attention.12 A recent investigation used patients following traumatic injury as a result of motor vehicle injury to assess the predictive power of the dorsolateral segment of the ACC. The dACC, which also communicates strongly with the mPFC, is considered to be a type of ‘neural alarm system’, encoding distress in both physical and social domains.13,14 Along with the insular cortex, it jointly commands the salience network of the brain, which directs attention to behaviorally relevant stimuli.15 The study concluded that dACC functional connectivity predicted long-term pain symptoms in 11 patients. Pain lasting beyond six months was most strongly predicted by weakened connectivity between the dACC and the precuneus – a part of the DMN that operates conjunctively with the mPFC and is highly involved in the individual subjective awareness of pain.16 The findings provide support for the previously specified framework underlying the systemic precursors of chronic pain, although the small sample size may warrant replication. Further insight into this neural model of chronic pain can help establish targets for intervention in at-risk patients. 

 

Cortisol Reactivity and Stress Mechanisms

Cortisol-driven stress mechanisms have also been shown to be highly involved in abnormal pain perception and hypersensitization, and contribute to unique predictive neuropathological pain models. In addition to mediating functional neuroplastic changes in corticolimbic circuitry associated with pathological pain, cortisol reactivity plays a role in anticipatory sensitization mechanisms linked to chronic stress and chronic pain.17 Turan et al. found that the initial cortisol response to a stimulus predicts progressive anticipatory sensitization in women. Larger cortisol responses (>.8 mg/mL) to an initial stressor were correlated with increasingly elevated cortisol levels before subsequent exposures. A smaller initial cortisol reactivity (< .77 mg/mL) preceded a negative trend in cortisol reactivity.18 Anticipatory stress and cortisol responses can also warp the perception and evaluation of pain stimuli; for example, both cortisol levels and subjective pain ratings intensify during the anticipation and active experience of uncontrollable electric shocks.19,20 This knowledge supports the fear-avoidance model of pain, which suggests that worsening or persisting pain symptoms develop through learned negative associations between pain and its context.21,22 A similar effect can be achieved via central sensitization, which may also play a role in chronic pain; however, its link to chronic pain is less understood. The upregulation of brain-derived neurotrophic factor by cortisol simultaneously contributes to the formation of a fear-based memory associated with pain while enhancing long-term potentiation of pain sensitivity mediated by the central nervous system, which becomes sensitized and easily activated, and manifests as chronic pain.23 Reducing stress levels and suppressing cortisol release during episodes of acute pain may decrease the sensitivity of the central nervous system to pain signals. This, in turn, may help to prevent the progression of acute to chronic pain. Taken together, these findings highlight the specialized role of hormonal stress factors in facilitating learning, negative evaluation, and sensitization in the context of chronic pain development.

The current understanding primarily implicates emotional processes rather than sensory mechanisms in the pathogenesis of chronic pain. According to Vachon-Presseau and his colleagues, the strongest predictor and amplifier is what they call the ‘emotional brain’ – namely, the corticolimbic system.24 The classical viewpoint suggests that central sensitization due to peripheral injury is the main factor that contributes to the development of chronic pain.25 A decade-old study titled OPPERA sought to reevaluate this hypothesis. This study followed thousands of healthy subjects for five years to track the development of first-onset persistent temporomandibular pain disorder (TMD). The results of psychophysical assessments contradicted the central sensitization hypothesis, as the authors found that pre-existing pressure pain thresholds poorly predicted the incidence of TMD.26 Similar findings were also observed in studies on chronic tension-type headaches, low back pain, and widespread pain.24 This suggests that the predictability of chronic pain based on brain parameters differs significantly from that of peripheral sensitivity. The underlying nature of chronic pain lies predominantly in perceptual factors arising from the mental catastrophization of noxious experiences.27 The learned aspects of chronic pain are heavily influenced by fear and other emotions. Consequently, chronic pain can most effectively be understood as a learned disruption in the subjective perception of pain over time. This is evident through the impact of reflexive, emotional processing in the mPFC and dACC, as well as the evaluative and anticipatory engagement of the NAc and cortisol. 

 

Mindfulness as a Preventative Measure

Mindfulness practice has become a trending topic in  chronic pain research, but its potential as a preventative measure remains unexplored. Mindfulness, defined as non-reactive and non-judgmental awareness of the present moment, plays a crucial role in preventing the escalation of negative emotional reactions and judgments of pain.28,29,30 Further insight into the therapeutic effects of meditation on neural mechanisms specifically relevant to the transition from acute to chronic pain presents an alternative solution to existing treatments for chronic pain, which tend to be costly and ineffective. Several studies have noted significant changes in key limbic and prefrontal regions as a result of short-term meditative practice. Just four 20-minute sessions of Samatha meditation mitigated mPFC response while bolstering ACC activity during pain.31 Increased pain-related ACC activation might be reflected in the predictive dACC – precuneus pathway. Multiple large-scale studies indicate that meditation and dispositional mindfulness are both negatively associated with amygdala volume, a feature noted in the findings of Vachon-Presseau as a positive predictor of chronic pain.11,32,33 A recently published, non-reviewed paper revealed that after a brief savoring meditation program, a significant increase in activation in the right NAc and deactivation in the right dlPFC were observed as a result of thermal stimulation during active meditation.34 The functional distinction between the dlPFC and the neighboring mPFC is still debated, although it is clear that the two are extremely interconnected and tend to function in unison.35 Inhibition of the dlPFC may reflect reduced emotional elaboration of the pain, while increased NAc recruitment during pain suggests an enhanced sensory experience perhaps through improved attention towards the stimulus itself. This aligns with findings that experienced meditators often report reduced unpleasantness, but not intensity, of pain.36 Increased connectivity between these two regions was also observed in participants who were asked to complete two weeks of at-home compassion-meditation training.37 Considering that a similar effect in the mPFC-NAc pathway has been shown to predict the persistence of pain, it would seem that enhanced functional connectivity within such a closely related network could likewise contribute to an increased predisposition to chronic pain. However, an alternative interpretation emerges when examining the distinction between the roles of the dlPFC and the mPFC in emotional processing. A recent study found that while the mPFC is involved in the arousal aspect of emotional stimuli, the dlPFC is important for balancing the value of emotions.35 While these two processes are certainly interwoven, it is worth considering that the mPFC may indiscriminately amplify pain signals with emotional valence, while improved dlPFC connectivity might correspond to an increased ability to manage the emotion associated with pain. Although the implications of some of these results vary by interpretation, they ultimately lend promise to the efficacy of short-term mindfulness training as a prescribed intervention method for use in clinical pain management.

 

Analysis of long-term changes in pain-related circuits found in experienced meditators proved to be more complicated. Overall, meditation seemed to affect activation and improve cortical thickness in the ACC and mPFC.38,39 Baseline activity in the amygdala and in the anterior midcingulate cortex (aMCC)–a region hosting the dACC–was negatively correlated with experience.40 During noxious stimulation, meditators show decoupling between the dACC and insular regions along with increased activation in the aMCC.40,41 Enhanced activity in the thalamus and insula and reduced activation in the mPFC and OFC are associated with lower reported pain.42 Individuals who scored higher on the Five Facet Mindfulness Questionnaire also exhibited increased pain thresholds explained by weaker connectivity between the central nodes of the default mode network – which include the mPFC, precuneus, and posterior parietal cortex – and stronger connectivity between the precuneus and somatosensory cortices.42 The majority of these findings were observed during a non-meditative state, indicating that long-term meditation training leads to sustained alterations in the subjective assessment of pain. However, conflicting evidence impedes the certainty of whether long-term meditation can reduce the risk of chronic pain. Though some improvements include a reduction in pain-related activation within the mPFC and decreased connectivity within the DMN, there is an observed elevation in baseline cortical density and activity in the mPFC. Reduced baseline activity in the dACC and amygdala are both implicated in the transition to chronic pain, and the simultaneous decoupling between the dACC and insula along with increased aMCC activity during pain further complicates previous conclusions. The literature on the neuroanatomy of long-term practitioners thus seems to contradict many of the potentially prescribable benefits of short-term mindfulness training.

 

The stress mechanisms underlying acquired fear of chronic pain are distinctly influenced by mindfulness-based interventions. Chronic pain is thought to be conditioned by fear, which is partially mediated through anticipatory sensitization. Turan et al. demonstrated that initial cortisol reactivity strongly predicted long-term trends in anticipatory cortisol levels in a series of stress-inducing tasks dispersed across several months. Higher initial pre-stressor cortisol values were correlated with significant progressive increases in pre-stressor cortisol values in controls compared to controls with low pre-stressor cortisol levels. Meditation and emotional skills training seemed to mitigate this effect in the second phase of this study. Between the first and second trials, subjects in the meditation group received 42 hours of training supplemented by optional at-home practice. The third trial took place five months after the training was completed. Subjects who displayed high anticipatory cortisol reactivity pre-meditation showed only marginal, non-significant increases across sessions, similar to the meditators with low pre-stressor cortisol. No initial differences were observed in pre-stressor or peak cortisol levels at Session 1 between the control and training groups.18 A reduction in baseline salivary cortisol at rest was also observed following a four-week regiment of transcendental meditation.44 These two lines of evidence demonstrate the potential implications of meditation on cortisol-related negative pain appraisal, as well as on the sensitization and chronification of pain.44,45 Moreover, these outcomes support the notion that mindfulness practice can inhibit the emotional learning effect of stress and aligns with research indicating that inadequate top-down inhibition contributes to the development of chronic pain, whereas enhancing inhibition protects against it.46,47 Stress and learning in the context of pain may thus be regulated by proper cognitive training.

 

Discussion

Given the novelty of this field, little research has provided a concrete understanding of the precursors and potential solutions for chronic pain development. Despite these limitations, the findings suggest that inhibition of cortisol-based fear conditioning as well as reduced activity in the medial prefrontal cortex as a result of meditative practice may contribute to a less negative appraisal of pain, thereby mitigating pathogenesis. Due to a lack of work specifically pertaining to the effects of meditation on the established predictive neurocircuitry, no direct link was found between meditation and functional connectivity in the dACC-precuneus or mPFC-NAc pathways. This evidence supports the need for further research to investigate the longitudinal effects of mindfulness training in preventing chronic pain and to better understand its underlying mechanisms. It is crucial to determine the exact timing of  transition to chronic pain. As advances in medicine aim to enhance population immunity through vaccine design, the well-being and physical health of the broader population could be significantly improved through the implementation of mindfulness-based interventions. Thus, further research should target the direct neural effects of mindfulness-based interventions in clinically at-risk populations to establish a connection between meditation and the persistence of pain. By shedding light on newly emerged biological markers of chronic pain within the context of meditation, this review seeks to encourage continued investigation into the potential benefits of mindfulness in preventing the development of chronic pain.

 

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Alexis Peetz Alio Mena Kassa