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The Chronic Stress of Chronic Pain: Clinical Implications

For many of our patients, chronic pain is a chronic stress. Unfortunately, the resulting ongoing physiological stress reaction can have neurotoxic influences in key brain regions, including the prefrontal cortex, amygdala and hippocampus, and drive maladaptive neuroplastic changes that may further fuel a chronic pain condition.1 For example, chronic stress generates extensive dendritic spine loss in the prefrontal cortex, hyperactivity in the amygdala, and neurogenesis suppression in the hippocampus.2,3,4 In parallel, patients with chronic pain have been shown to exhibit reduced gray matter in the prefrontal cortex, increased neuronal excitability in the amygdala and reduced hippocampal neurogenesis.5,6,7

These three brain areas have been identified to play an important role in fear learning and memory.8 Modulated by stress hormones and stress-induced neuroplastic changes, stress may:
(a) enhance the memory of the initial pain experience at pain onset
(b) promote the later persistence of the pain memory
(c) impair the memory extinction process and the ability to establish a new memory trace.9

Sections of the brainIn other words, an ongoing stress reaction, triggered by distressing cognitions and emotions in response to pain or other life circumstances, could reinforce and strengthen the memory of pain. The experience of pain could be generated not by nociceptive activity, but by a well-established memory of pain and inability of the brain to create new associations. Leading researchers in the cortical dynamics of pain at Northwestern University suggest this learning process and persistence of pain memory could be a major influencing mechanism driving chronic pain.9,10

In addition, neurogenesis suppression in the hippocampus is associated with depression, while increased amygdala excitability is associated with anxiety, two mood disorders that frequently accompany and complicate chronic pain conditions.11,12

Why is this important? Appreciating the complex factors that contribute to chronic pain conditions can point to treatment strategies that address these factors.13 For example, strategies that help reduce a patient’s stress reaction, mitigate the experience of fear and anxiety, and/or promote relaxation, positive mood and self-efficacy could conceivably reduce the stress reaction and reverse maladaptive neuroplasticity. While chronic pain is a multifaceted and highly complex condition with no simple answers or one-size-fits-all successful treatment strategy, initial research suggests promise for this approach to modulate cortical structure. In a study of cognitive-behavioral therapy (CBT) in the treatment of chronic pain, an 11-week CBT treatment course increased gray matter in the prefrontal cortex and hippocampus.14

In addition, a systematic review of brain changes in adults who participated in Mindfulness-Based Stress Reduction identified increased activity, connectivity and volume in the prefrontal cortex and hippocampus in stressed, anxious and healthy adults.15 Also, the amygdala demonstrated decreased activity and improved functional connectivity with the prefrontal cortex. Although yet to be studied in patients with chronic pain, these neuroplastic changes could potentially promote improved cortical dynamics in our patients.

I am excited to share this model of chronic stress and chronic pain and evidence-based applications of mindfulness to pain treatment in my upcoming course Mindfulness-Based Pain Treatment in Arlington, VA August 4 and 5, 2018 and in Seattle, WA November 3 and 4, 2018. Course participants will learn about mindfulness and pain research, practice mindful breathing, body scan and movement and expand their pain treatment tool box with practical strategies to improve pain treatment outcomes. Research examining the application of mindfulness in the treatment of patients at risk of opioid misuse will be included. I hope you will join me!


Vachon-Presseau E. Effects of stress on the corticolimbic system: implications for chronic pain. Prog Neuropsychopharmacol Biol Psychiatry. 2017; Oct 25. pii: S0278-5846(17)30598-5.
Arnsten AF. Stress signaling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 2009:10(6):410-422.
Zhang X, Tong G, Guanghao Y, et al. Stress-induced functional alterations in amygdala: implications for neuropsychiatric diseases. Front Neurosci. 2018 May 29;12:367.
Kim EJ, Pellman B, Kim JJ. Stress effects on the hippocampus: a critical review. Learn Mem. 2015;22(9):411-6.
Fritz HC, McAuley JH, Whittfeld K, et al. Chronic back pain is associated with decreased prefrontal and anterior insular gray matter: results from a population-based cohort study. J Pain. 2016;17(1):111-8.
Veinante P, Yalcin I, Barrot M. The amygdala between sensation and affect: a role in pain. J Mol Psychiatry. 2013;1(1):9.
Vachon-Presseau E. Roy M, Martel MO, et al. The stress model of chronic pain: evidence from basal cortisol and hippocampal structure and function. Brain. 2013;136(Pt 3):815-27.
Greco JA, Liberzon I. Neuroimaging of fear-associated learning. Neuropsychopharmacology. 2016;41(1):320-334.
Mansour AR, Farmer MA, Baliki. Chronic pain: role of learning and brain plasticity. Restor Neurol Neurosci. 2014;32(1):129.
Baliki MN, Apkarian AV. Nociception, pain, negative moods and behavior. Neuron. 2015;87(3):474-491.
Schmaal L, Veltman DJ, van Erp TG, et al. Subcortical brain alterations in major depressive disorder: findings from ENIGMA major depressive disorder working group. Mol Psychiatry. 2016;21(6):806-12.
Shin LM, Liberzon I. The neurocircuitry of fear, stress and anxiety disorders. Neuropsychopharmacology. 2010;35(1):169-91.
Greenwald J, Shafritz KM. An integrative neuroscience framework for the treatment of chronic pain: from cellular alterations to behavior. Front Int Neurosci. 2018 May 23;12:18.
Seminowicz DA, Shpaner M, Keaser ML, et al. Cognitive-behavioral therapy increases prefrontal cortex gray matter in patients with chronic pain. J Pain. 2013;14(2):1573-84.
Gotink RA, Meijboom R, Vernooij, et al. 8-week Mindfulness Based Stress Reduction induces brain changes similar to traditional long-term meditation practice – A systematic review. Brain Cogn. 2016;108:32-41.

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