What is the Connection Between Anxiety, Depression, and Pain?

Question:

"Several of my depressed patients report worsening of their pain symptoms with exacerbation of anxiety and depression. What is the connection between anxiety, depression, and pain?"

Vladimir Maletic, MD:

The overlap of anxiety, depression, and pain is more a rule than an exception. Epidemiologic studies suggest that 30% to 60% of patients with depression also suffer from a painful condition. Presence of pain is a major predictor of depression and anxiety. A group of authors reported a type of "dose-response" relationship: the more bodily regions impacted by pain, the greater the prevalence of generalized anxiety disorder and major depressive disorder (MDD). ¹ Furthermore, symptom severity in depression, anxiety, and sleep disorders predicted onset of chronic widespread pain in a 15-month prospective study. ² It is becoming clear that the relationship between MDD, anxiety, and pain runs far below the surface.

Brain circuitry involved in regulation of emotions and stress response, to a significant degree, overlaps with components of the "pain matrix" involved in emotional and cognitive aspects of pain processing. Having in mind the evolutionary value of pain, stress, and emotions–mobilizing the organism to organize and execute an adaptive response–it would not be a surprise if nature, parsimoniously, selected overlapping pathways. ³

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There are important distinctions in the processing of pain, emotions, and stress response, pain sensory areas (thalamus, SI and SII) are less involved in the pathogenesis of depression and anxiety. There is a striking similarity regarding the involvement of limbic areas and paralimbic prefrontal cortex (amygdala, hippocampus, insula, anterior cingulate cortex [ACC], ventromedial prefrontal cortex [vmPFC]), as well as more "cognitive" and integrative areas, such as rostral ACC (rACC), dorsal ACC (dACC), dorsomedial PFC (dmPFC), and dorsolateral PFC (dlPFC). ^4-6 Pain, anxiety, and depressed mood appear to have an overlapping capacity to engage autonomic, neuroendocrine, and neuroimmune components of stress response. MDD, anxiety disorders, and chronic pain conditions are all associated with altered sympathetic/parasympathetic balance, neuroendocrine disturbance, reflected in insufficient hypothalamic-pituitary-adrenal regulation, and enhanced proinflammatory response. ^7,3 Given that these conditions have shared pathophysiological underpinnings, overlapping symptomatic manifestations should be no surprise. Full understanding of this "synergy" may have critical treatment implications.

–Vladimir Maletic, MD

References

1. Manchikanti L, Pampati V, Beyer C, Damron K . Do number of pain conditions influence emotional status. Pain Physician . 2002;5(2):200-205.
2. Gupta A, Silman AJ, Ray D, et al . The role of psychosocial factors in predicting the onset of chronic widespread pain: results from a prospective population-based study. Rheumatology (Oxford) . 2007;46(4):666-671.
3. Maletic V, Raison CL . Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci . 2009;14:5291–5338.
4. Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ . A meta-analytic study of changes in brain activation in depression. [Published erratum in Hum Brain Mapp . 2008;29(6):736.] Hum Brain Mapp . 2008;29(6):683-695.
5. Etkin A, Wager TD . Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry . 2007;164(10):1476-1488.
6. Baliki MN, Chialvo DR, Geha PY, et al . Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci . 2006;26(47):12165-12173.
7. Alesci S, Martinez PE, Kelkar S, et al . Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab . 2005;90(5):2522-2530.