Comorbidities and the complexities of chronic pain.

675 October 2014 I RRESPECTIVE of their underlying mechanisms, many chronic pain syndromes share several comorbidities. These comorbidities include mood alterations (such as depression), anxiety, sleep disturbances, fatigue/lack of energy, neurocognitive changes, and other vague symptoms including generalized diffuse pain states. These comorbidities reduce the quality of life of the patient with chronic pain and by themselves cause the loss of working days and obstruct the living of a healthy social life. In this issue of AnESThESIology, Tajerian et al.1 report on a set of experiments in a mouse model of Complex Regional Pain Syndrome type 1 (CRPS1). The authors show that CRPS1related pain coincides with increased anxiety and memory impairment. Importantly, brain histology and brain protein assays show that the CRPS animals display signs of plastic changes and reduced synapse formation and neurotrophy, indicative of neural plasticity, in areas of the brain involved in emotion, anxiety, fear and mood (amygdala), and cognition/memory (hippocampus and perirhinal cortex). These are important observations as they show conclusively that comorbidities in complex chronic pain syndromes, in this case, a surrogate model of CRPS1, have a pathophysiological substrate in the brain that may be an important target for intervention. It is known for decades that the occurrence of chronic pain and neuropsychiatric disease, most importantly depression, is highly comorbid.2 Indeed, on average up to 50% of patients with some form of chronic pain display symptoms of anxiety and depression,3 whereas in some studies the number exceeds 75%.4 A recent Canadian study showed that chronic pain of any kind is associated with the development of major depression within 2 yr in 16.4% of patients.2 Importantly, the prevalence of major depression increased with greater pain severity. These findings are in agreement with those in the study by Tajerian et al., showing that the temporal relationship between chronic pain and neurocognitive dysfunction is such that anxiety and memory impairment are secondary to the induction of experimental CRPS1. Still, the reverse is similarly true. For example, individuals without pain but diagnosed with major depression are almost three times more likely to develop musculoskeletal pain within a 2-yr time span than nondepressed persons.2 Also anxiety affects pain perception in the brain. These studies demonstrate important coherent neural pathways exemplifying the impact of anxiety and depression on pain and vice versa. A key component in the precipitating property of depression during chronic pain results from observations that brain inflammation after peripheral nerve injury contributes to the development of depressionlike behavior, with increased cytokine expression in specific brain areas.5 Importantly, antagonizing the neuroinflammatory response ameliorates the effects of neuropathic pain on depression.5 In line with these animal data, peripheral release of proinflammatory cytokines including tumor necrosis factor-α is observed in a subset of patients with CRPS1,6 and these cytokines may be an initial causative factor in the central defects in cognition and mood alteration in a way similar to that observed in postoperative states.7 of interest is further that stress is known to contribute to the development of depression as well as chronic pain.8 For example, in animals, stress exacerbates both pain and depression-like behavior.5 In humans, a healthy stress response, through activation of the hypothalamo–pituitary–adrenal axis, will initiate a cascade of adaptive responses aimed at enhanced cognitive performance and modified cardiovascular and immune functions.8 Activation of the hypothalamo–pituitary–adrenal axis and the sensation of acute pain after tissue damage are two highly functional and protective responses that allow the individual to focus attention toward the tissue damage, if necessary take evasive action and seek help. In contrast, because of chronic stress and chronic pain the hypothalamo–pituitary–adrenal axis becomes dysfunctional resulting in either hyperor hypocortisolemia.8 Both of which are thought to be associated with mood disturbance. Tajerian et al.1 observed reductions in the brain growth factor, brain-derived neurotrophic factor, and synaptic Comorbidities and the Complexities of Chronic Pain