A complex relationship and a daunting clinical challenge
Chronic pain enhances the risk of MDD by 2-fold to 5-fold. The risk appears to be mediated by the number of pain conditions rather than by the severity of pain.23 Some authors have noted a kind of dose-response relationship among pain, depression, and anxiety. Among patients who experienced chronic pain that affected 1 body region, the prevalence of generalized anxiety disorder (GAD) and MDD was 30% and 20%, respectively; in patients who experienced pain in ≥2 regions, the prevalence of GAD and MDD was elevated to 54% and 32%.25 Moreover, patients with fibromyalgia were 4.3 times more likely than healthy controls to develop MDD at some point in their lives and 4.7 times more likely to develop an anxiety disorder.26
Although women are more likely to suffer from fibromyalgia, the risk for people of either sex of developing subsequent MDD is comparable once the condition has developed.27 Overall, depression and anxiety are among the most common comorbidities of fibromyalgia, with prevalence ranging from 20% to 80% and 13% to 63.8%, respectively.28
High comorbidity between depression and pain also is relevant for patients with neuropathic pain. A survey from Australia reported depression in 34% and anxiety in 25% of patients with neuropathic pain.29 Pain severity tended to be enduring and associated with significantly impaired functioning. A significant percentage of patients suffering from rheumatoid arthritis and systemic lupus erythematosus tend to manifest anxiety and depression (93% to 94%), cognitive impairment (66%), fatigue (40%), and sleep disorders (72%).22
The relationship between depression and pain appears to be bidirectional. For example, recent studies demonstrate that 30% to 60% of depressed patients also suffer from a painful condition.5
The complex history of patients presenting with concomitant complaints of depression, anxiety, chronic pain, sleep disturbance, cognitive impairment, and fatigue present a daunting diagnostic task. Pain tends to be associated with greater fatigue and sleep disturbance, which in turn depletes a patient’s ability to enjoy life and enhances negative affect.19,20,30 The take-home message might be to screen all chronic pain patients for MDD, anxiety, and sleep disorders, and vice versa.
Furthermore, comorbidity among chronic pain, MDD, anxiety, and sleep disorders can introduce specific intricacies into our treatment approach. Although, in general, comorbidities tend to have a negative impact on treatment outcomes, many pharmacotherapeutic and non-drug interventions targeting chronic pain might ameliorate sleep problems, low energy, anxiety, depression, and anhedonia.18,20,30-32 On the other hand, we should consider that opioid treatment for chronic pain might represent a risk factor for subsequent depression. It is conceivable that chronic opioid treatment and associated sedation can erode self-efficacy and social relationships, thereby compromising sources of support.33,34 It is equally important to keep in mind that, even if we are successful in attaining remission when treating depression and pain, residual pain symptoms might persist, requiring more specific interventions.24
MDD and chronic pain each have, on their own, a well-established association with suicide attempts and completion. Researchers are investigating whether a pathophysiologic suicide-promoting synergy between the 2 disorders exists when they are comorbid (Box35-37).
Shared genetics and pathophysiology
Several candidate genes have been identified as risk genes for chronic pain, depression, and anxiety. One of those studied the most is 5-HTTLPR, involved in regulating synthesis of serotonin transporter. The short form of this gene has been implicated in a diverse set of conditions, including MDD, anxiety disorders, and substance abuse—and fibromyalgia. Other genes associated with the risk of MDD and pain disorders are ones that code for:
- serotonin 5-HT2A and 5-HT1A receptors
- catechol-O-methyltransferase, an enzyme involved in catecholamine metabolism
- dopamine D4 receptor
- proinflammatory cytokines interleukin-1 and interleukin-6.4
Both monoamines and inflammatory cytokines play a role in modulating γ-aminobutyric acid (GABA) and glutamate neurons, as well as glia cells constituting peripheral pain pathways and central circuits that participate in the pain response and regulation of mood.4,17,38
The ‘pain matrix’
Brain circuitry that is involved in processing pain stimuli—often referred to as the pain matrix—shares many structural components with circuitry involved in the stress response and emotional modulation.4 Emerging evidence indicates that the pain matrix might not be pain-specific but, instead, a complex aggregate of interconnected brain structures involved in evoking defensive responses to a number of offending stimuli, including pain, threat, danger, loss, and social rejection or isolation.
It is remarkable, in this regard, that imaging studies show that the dorsal anterior cingulate, central to experiencing negative affect in response to physical pain, also mediates distress in response to the “pain” of social exclusion.39 Emerging functional and structural imaging provides evidence of continuous reorganization of prefrontal cortices as a consequence of enduring chronic pain.1 Of particular interest are findings of (1) a reduction of gray matter in the dorsolateral prefrontal cortex (DLPFC) and (2) functional activation of the medial prefrontal cortex (mPFC), both of which correlate with the duration and experience of chronic back pain.1 It is tempting to speculate that structural decline of the DLPFC, observed in MDD and chronic pain, is linked to cognitive and executive function deficits, which are readily observed in patients with either disorder—given that DLPFC is a “hub” of the so-called “cognitive-executive functional network.”1,4