Exploring the Connections Between Neuropathic Pain and Comorbid Mood Disorders

Neuropathic pain has been linked with a range of negative outcomes, including worse quality of life and health-related quality of life compared with the general population, as well as greater sleep impairment, lost workdays, and psychological distress.^1,2 The presence of both sensory and affective disturbances in neuropathic pain suggests shared mechanisms with mood disorders, and a substantial body of research supports this notion.

A review published in Pain and Therapy in December 2017 explored this connection, along with the proposed underlying mechanisms and available treatment options.³

Previous studies indicate associations between neuropathic pain and anhedonia, depression, cognitive impairment, decreased motivation and appetite, and more.⁴ In rodent models, neuropathic pain was found to be associated with changes in the expression of genes that have been implicated in chronic pain, depression, and anxiety in humans. These changes were observed in the nucleus accumbens, medial prefrontal cortex, and periaqueductal gray, structures that are involved in the processing of mood, reward, and motivation.⁵

Particularly strong associations have been noted between pain and depression and anxiety.⁶ Neuropathic pain is correlated with higher rates of depression and anxiety,^7-9 and depression has been found to predict pain in multiple sclerosis and Parkinson disease. Studies have also revealed a connection between anxiety and pain intensity in patients with pain disorders.^7,10

Shared mechanisms

Evidence points to a role for supraspinal neuroinflammation in the pathogenesis of affective disorders in patients with neuropathic pain. Preclinical studies indicate that nerve injury is a result of neuroinflammation in affective areas of the forebrain,⁴ “shown to underlie the development of affective disturbances by disrupting critical physiological processes” such as those summarized below, the study researchers reported.

• Peripheral inflammation and affective disturbances. Peripheral inflammation can trigger “sickness behavior,” which includes symptoms such as pain, fatigue, affective disturbances, and sleep dysfunction. Increased levels of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) have been observed in patients with major depressive disorder, and higher levels of TNF were found in patients with comorbid neuropathic pain, compared with patients with pain without depression.¹¹ These findings may reflect shared inflammatory mechanisms between mood disorders and neuropathic pain.
• Immune-to-brain signaling and inflammatory cytokines as neuromodulators. “Supraspinal cytokines and chemokines are thought to act as neuromodulators within a cytokine network of neurons, microglia and astrocytes, acting to regulate cytokine production and cytokine receptor expression, and both amplifying and attenuating cytokine signals,” noted the review authors. “Nerve injury-evoked supraspinal neuroinflammation appears to disturb physiological cytokine concentrations, causing a ‘sub-inflammatory’ response.”⁴ Especially strong patterns of expression have been found in the hippocampus, amygdala, and other regions involved in affect regulation. 
• Inflammatory cytokines and affective disturbances in the neuropathic brain. Recent results support the possibility that neuroinflammation in key brain areas influences the development of affective disturbances. For example:
  
  • Nerve-injury induced neuroinflammation in the medial prefrontal cortex, hippocampus, ventral postero-lateral thalamus, and brainstem has been linked with hyperalgesia and allodynia⁴
  • Associations have been found between TNF modulation of the dopaminergic systems and blunted reward
  • Evidence suggests that midbrain glial activation may contribute to midbrain cell death and alterations in glucocorticoid expression that have been implicated in affective disturbances⁴

Antidepressants and pain

Considering the apparent connection between pain and mood disorders, some patients require an integrated approach to address both conditions. Psychological treatment may include cognitive behavioral therapy, brief psychodynamic psychotherapy, and medication. Tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors are the two classes of psychoactive drugs that have demonstrated efficacy for pain in randomized controlled trials. These agents are considered first-line therapies for neuropathic pain.^12,6 Some results show promise for combination therapy with antidepressants and anticonvulsants, which may be more effective than monotherapy, although more research is needed to definitively suppport this approach.

For additional insight into the topic, Clinical Pain Advisor talked with Heather Tick, MD, clinical associate professor in the department of family medicine and the department of anesthesiology and pain medicine at the University of Washington in Seattle, and the university’s first holder of the Gunn-Loke Endowed Professorship of Integrative Pain Medicine.

Clinical Pain Advisor: What is known about the role of emotion in neuropathic pain and the link with mood disorders?

Dr Tick: We know from animal studies that stress can cause the nervous system to become more sensitized to pain. This is part of the central sensitization phenomenon when the mechanisms that are designed to inhibit non-life-threatening pain are shut down. Mood disorders are also associated with increased pain, and addressing mood disorders can improve pain outcomes. Sometimes patients use pain drugs to treat their mood and anxiety without realizing this. 

Clinical Pain Advisor: What are the key takeaways for clinicians treating patients with neuropathic pain?

Dr Tick: Multimodal care is essential to effective pain care. The idea of a quick fix through a drug or many drugs has been shown to be inadequate. Chronic pain is complex and requires time and a variety of strategies. Most of all, patients need to recognize that they have to be in charge of their daily choices to keep themselves healthy. You can’t go to the dentist twice a year and expect to have healthy teeth if you do not brush your teeth every day as well. 

Clinical Pain Advisor: What should be next steps in this area, in terms of research or otherwise?

Dr Tick: In general, as a nation we need to begin to promote healthy lifestyle choices rather than convenience. We have to wake up and see that our life expectancy is going down compared with other developed nations, even though we spend twice as much on healthcare once people get sick. We do not have a winning strategy. We do have research showing the benefits of manual therapies, yoga, tai chi, nutrition, and healthy lifestyle. 

The lead review author, R. Torta, has received an honorarium from Pfizer.  

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References

1. Meyer-Rosberg K, Burckhardt CS, Huizar K, Kvarnström A, Nordfors LO, Kristofferson A. A comparison of the SF-36 and Nottingham Health Profile in patients with chronic neuropathic pain. Eur J Pain. 2001; 5(4):391-403.
2. Inoue S, Taguchi T, Yamashita T, Nakamura M, Ushida T. The prevalence and impact of chronic neuropathic pain on daily and social life: a nationwide study in a Japanese population. Eur J Pain. 2017;21(4):727-737. 
3. Torta R, Ieraci V, Zizzi F. A review of the emotional aspects of neuropathic pain: from comorbidity to co-pathogenesis. Pain Ther. 2017; 6(Suppl 1):11–17.
4. Fiore NT, Austin PJ. Are the emergence of affective disturbances in neuropathic pain states contingent on supraspinal neuroinflammation? Brain Behav Immun. 2016;56:397-411. 
5. Descalzi G, Mitsi V, Purushothaman I, et al. Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression. Sci Signal. 2017; 10(471):eaaj1549.
6. Aloisi AM, Berlincioni V, Torta R, et al; Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN). The role of gender, psycho-social factors and anthropological-cultural dimensions on pain in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation. Eur J Phys Rehabil Med. 2016; 52(5):730-740.
7. Radat F, Margot-Duclot A, Attal N. Psychiatric co-morbidities in patients with chronic peripheral neuropathic pain: a multicentre cohort study. Eur J Pain. 2013;17(10):1547-1557.
8. Shaygan M, Böger A, Kröner-Herwig B. Clinical features of chronic pain with neuropathic characteristics: a symptom-based assessment using the pain DETECT questionnaire. Eur J Pain. 2013; 17(10):1529-1538. 
9. Uher T, Bob P. Neuropathic pain, depressive symptoms, and C-reactive protein in sciatica patients. Int J Neurosci. 2013; 123(3):204-208.
10. McWilliams LA, Goodwin RD, Cox BJ. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain. 2004; 111(1-2):77-83.
11. Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev. 2014; 66(1):80–101.
12. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015; 14(2):162-173.