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The Comorbidity of Chronic Pain and Depression


Pain and depression represent some of the most common reasons people seek out medical attention.[i] There is also a high rate of comorbidity with the two conditions. Approximately 50-60% of people who are treated for depression also report problems with aches and discomfort.[ii],[iii]  The presence of depression predicts a higher likelihood of discomfort which in turn indicates a greater chance of depression.[iv],[v],[vi],[vii] Unfortunately, when these conditions are comorbid, the identification and effective treatment of depression is reduced.[viii],[ix] Additionally, studies have found that when people experience both depression and pain together, they are more likely to have limited ability at work and with daily-living activities than those with depression alone.[x],[xi] They are also more likely to lose employment or insurance.[xii]

Models of Chronic Pain and Depression

The association between pain and depression can be observed directly using animal models. Evidence suggests that depression can exacerbate issues with pain. Wistar-Kyoto rats are bred to display hormonal and behavioral imbalances that mimic human patients with depression. Studies have found that these depressed rats have an increased sensitivity to pain when compared with other breeds.[xiii] Pain can also lead to depression. Researchers have found that experimentally induced neuropathic or inflammatory pain can lead to symptoms of depression in mice.[xiv],[xv]

Comorbid Chronic Pain and Depression Alter the Brain

This close relationship between pain and depression suggests common underlying mechanisms of the pathology of both conditions. Neuroimaging shows that pain perception and depression are both associated with multiple brain regions and pathways, including the prefrontal cortex (PFC), the nucleus accumbens (NAc), the amygdala, and the hippocampus.[xvi],[xvii]

Pain, of course, has a sensory aspect to its experience—the feelings of physical pain. However scientists also recognize the affective aspect of pain, which is annoyance, sadness, or depression in response to pain.[xviii] When acute pain becomes chronic pain, people may transition from having a primarily sensory experience of pain, to having an affective experience; it is then that depression commonly develops.[xix],[xx] It is during this stage that changes are seen in the NAc and the amygdala relating to anhedonia (loss of pleasure) and disordered mood, respectively.[xxi],[xxii] The cognitive and emotional impairment present in chronic pain conditions is also evidenced by decreased hippocampal volume.[xxiii]

Chronic Pain, Depression, and Neurotransmitters

Comorbid pain and depression can even change the brain on the molecular level, disrupting neurotransmitter pathways. Altered glutamate signaling has been associated with both depression and pain.[xxiv],[xxv] Decreased glutamate receptor levels in the PFC, hippocampus, and amygdala have been found in multiple rat studies of stress-induced depression.[xxvi] New studies suggest that glutamate neurotransmission in the NAc can specifically relieve the depressive symptoms of chronic pain.[xxvii]

The monoamine neurotransmitters also play a role in the pathology of both pain and depression. Low norepinephrine is often associated with depression, and norepinephrine also has pain relieving effects when it binds to α2 receptors.[xxviii] Dysfunctional dopamine neurotransmission can trigger depressive symptoms.[xxix] Dopamine is also implicated in chronic pain conditions, such as osteoarthritis, headache, and fibromyalgia.[xxx] The role of serotonin as a modulator of both mood and pain perception is well documented.[xxxi],[xxxii] The IDO1 enzyme is responsible for directing tryptophan down the kynurenine pathway, instead of converting it into serotonin. IDO1 activity is associated with decreased serotonin, increased kynurenine, and depressed mood.[xxxiii],[xxxiv] Studies have found that IDO1 inhibition improves pain-related depression.[xxxv]

Comorbidity of Chronic Pain and Depression: Traditional and Functional Treatments

Traditional treatments for chronic pain with depression include pharmaceutical drugs that target areas of neurotransmitter imbalance. Serotonin and norepinephrine reuptake inhibitors increase the extracellular levels of both serotonin and norepinephrine, and they are commonly used for depression. They are also used in the treatment of neuropathic pain, such as diabetic neuropathy and fibromyalgia.[xxxvi] However, when pain and depression are comorbid, patients often have a reduced response to treatment.[xxxvii],[xxxviii] Furthermore, studies have found that chronic pain conditions increase the risk of recurrence with depression, even among patients who are in remission.[xxxix],[xl] Thus, it is important for patients with comorbid depression and chronic pain to find effective therapies.

One study by Hopton et. al. compared the outcomes of patients with comorbid depression and pain and patients with depression alone using either acupuncture, counseling, or traditional care. They found that compared to traditional therapy, both acupuncture and counseling were effective for the treatment of depression, with or without comorbid pain.[xli] Patients with pain received greater reductions in their depression using acupuncture, than those using counseling or traditional treatments.[xlii] All three treatments reduced pain. However, acupuncture was most effective after 6-9 months.[xliii]

Understanding how comorbid pain and depression influence brain chemistry, and how they affect clinical outcomes is an important first step for helping these complex patients to find relief and balance.

[i] Li, J. X. (2015). Pain and depression comorbidity: A preclinical perspective. Behavioural brain research, 276, 92-98.

[ii] Doan, L., Manders, T., & Wang, J. (2015). Neuroplasticity underlying the comorbidity of pain and depression. Neural plasticity2015.

[iii] Hopton, A., MacPherson, H., Keding, A., & Morley, S. (2014). Acupuncture, counselling or usual care for depression and comorbid pain: secondary analysis of a randomised controlled trial. BMJ open, 4(5), e004964.

[iv] Li op. cit.

[v] de Heer, E. W., Gerrits, M. M., Beekman, A. T., Dekker, J., van Marwijk, H. W., de Waal, M. W., … & van der Feltz-Cornelis, C. M. (2014). The association of depression and anxiety with pain: a study from NESDA. PloS one, 9(10), e106907.

[vi] Emptage, N. P., Sturm, R., & Robinson, R. L. (2005). Depression and comorbid pain as predictors of disability, employment, insurance status, and health care costs. Psychiatric services, 56(4), 468-474.

[vii] Doan op. cit.

[viii] de Heer op. cit.

[ix] Emptage op. cit.

[x] Ibid.

[xi] Doan op. cit.

[xii] Emptage op. cit.

[xiii] Li op. cit.

[xiv] Li op. cit.

[xv] Walker, A. K., Kavelaars, A., Heijnen, C. J., & Dantzer, R. (2014). Neuroinflammation and comorbidity of pain and depression. Pharmacological reviews, 66(1), 80-101.

[xvi] Doan op. cit.

[xvii] Walker op. cit.

[xviii] Doan op. cit.

[xix] Ibid

[xx] Li op. cit.

[xxi] Doan op. cit.

[xxii] Li op. cit.

[xxiii] Doan op. cit.

[xxiv] Li op. cit.

[xxv] Doan op. cit.

[xxvi] Ibid

[xxvii] Ibid

[xxviii] Ibid

[xxix] Ibid

[xxx] Ibid

[xxxi] Ibid

[xxxii] Li op. cit.

[xxxiii] Ibid

[xxxiv] Doan op. cit.

[xxxv] Ibid

[xxxvi] Ibid

[xxxvii] de Heer op. cit.

[xxxviii] Emptage op. cit

[xxxix] Gerrits, M. M., van Oppen, P., Leone, S. S., van Marwijk, H. W., van der Horst, H. E., & Penninx, B. W. (2014). Pain, not chronic disease, is associated with the recurrence of depressive and anxiety disorders. BMC psychiatry, 14(1), 187.

[xl] de Heer op. cit.

[xli] Hopton, A., MacPherson, H., Keding, A., & Morley, S. (2014). Acupuncture, counselling or usual care for depression and comorbid pain: secondary analysis of a randomised controlled trial. BMJ open, 4(5), e004964.

[xlii] Ibid

[xliii] Ibid

Clinical Contributor

Marina Braine

Clinical Support Specialist at Sanesco International, Inc.

Marina Braine is a Clinical Support Specialist at Sanesco. She graduated from UNC-Asheville with her Bachelors of Science in Biology with a minor in French. She likes to keep active by hiking, running, and contra dancing around Asheville.


Ramona Richard, MS, NC

Ramona Richard, MS, NC

Ramona Richard graduated with honors from the University of California with a Bachelor’s Degree in psychology and graduated summa cum laude with a Master’s Degree in Health and Nutrition Education. She also holds a Standard Designated Teaching Credential from the State of California, is a California state-certified Nutrition Consultant and a member of the National Association of Nutrition Professionals.

Ramona has participated in nutrition education in both public and private venues, including high school and college presentations, radio and public speaking for the past 20 years. She is the owner of Radiance, a nutrition consulting company, the Director of Education for Sanesco International, and a medical technical writer.

Disclaimer: The information provided is only intended to be general educational information to the public. It does not constitute medical advice. If you have specific questions about any medical matter or if you are suffering from any medical condition, you should consult your doctor or other professional healthcare provider.

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