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Selecting an Antidepressant for Pain Patients

The potential loss of brain tissue should motivate all pain clinicians to look for undiagnosed mood disorders. Treating both pain and mood disorders aggressively will increase the likelihood of a better outcome. Not treating, or undertreating either, will most likely result in treatment failures for both conditions.
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Quality of life is one of the primary motivations for human productivity. There are many encumbrances to this quest in life and two of the more debilitating conditions that will prevent a person from having an optimal quality of life are chronic pain and depression. The devastation to one’s happiness is compounded by the co-morbidity of these two insidious processes. There appears to be some evidence that the neurobiological underpinnings of each are similar and one may predispose a patient to the other.

Epidemiology and Comorbidity

The Medical Outcomes Study of over 11,000 patients illustrated that the effect of Major Depressive Disorder (MDD) on quality of life and functional impairment equals or exceeds the impairment seen in general medical conditions such as diabetes.1 Treatment of MDD remains problematic as shown by the National Comorbidity Study in which approximately half of those surveyed who had been diagnosed with MDD in the preceding twelve months and had not received any treatment for it.2 Of those who received treatment, about 42% of those were deemed to have received minimally adequate treatment.

Painful symptoms are very prevalent in patients with MDD. Two-thirds of patients with MDD also experienced pain symptoms in a major meta-analysis.3 Pain symptoms measured were headache, neck, back, joint, extremity, abdominal, pelvic and general pain. The prevalence rates in both psychiatric and non-psychiatric settings were similar. The baseline intensity of pain also predicts the treatment outcome of chronic pain patients with MDD treated with selective serotonin reuptake inhibitors (SSRI). The odds ratios for patients with MDD having a poor response to treatment and baseline mild, moderate or severe co-morbid pain were 1.5, 2.0 and 4.1, respectively, compared to patients with MDD and no pain.4

The Midlife Development in the United States Study (MIDUS) studied over 3,000 patients with arthritis, migraine and back pain. Linear regression analysis revealed significant positive associations between each pain condition and MDD with odds ratios of 2.07, 2.39 and 2.06, respectively.5 A community-based study of over 91,000 elderly patients with disabling low back pain and depressive symptoms examined the co-morbidity of one condition with the other. Results showed that baseline depressive symptoms increased the odds of disabling low back pain after two years and that baseline disabling low back pain increased the odds of depression after two years.6

Not only is the frequency of depression higher in chronic painful conditions and vice-versa, but the co-occurrence of depression and anxiety is associated with higher levels of pain severity and impairment from pain.7 Pain severity in diabetic peripheral neuropathy affects symptom levels of depression, anxiety, and sleep, as well as patient functioning.8

Brain Areas Involved in Mood Regulation

There are five key areas of the brain that are involved with the regulation of mood:

  • Ventromedial prefrontal cortex (VMPFC)
  • Lateral orbital prefrontal cortex (LOPFC)
  • Dorsolateral prefrontal cortex (DLPFC)
  • Amygdala
  • Hippocampus

The ventromedial prefrontal cortex (VMPFC) modulates pain, aggression, sexual and eating behaviors as well as autonomic and neuroendocrine responses.9 The lateral orbital prefrontal cortex (LOPFC) is involved with correcting and inhibiting maladaptive, perseverative and emotional responses. Its activity is increased in MDD, obsessive compulsive disorder, post-traumatic stress disorder and panic disorder.10 The dorsolateral prefrontal cortex (DLPFC) is involved with manipulation of information in working memory, cognitive control and solving complex tasks. Hypoactivity of the DLPFC is associated with the neuropsychological symptoms seen in MDD.11 The amygdala is involved with the regulation of cortical arousal and the neuroendocrine response to ambiguous and surprising stimuli. In addition, it is involved with the regulation of emotional learning and memory and the tendency to ruminate on unpleasant memories.12 The degree of depressive symptoms correlates with the activation of the amygdale.13 The hippocampus plays a role in contextual learning and memory and its dysfunction may play a role in inappropriate emotional responses. The hippocampus is rich in glucocorticoid receptors and is involved in the regulatory feedback to the hypothalamic-pituitary-adrenal axis (HPA).14,15

Brain Structural Changes

Regional cerebral blood flow (CBF) differences have been shown between patients with MDD and healthy controls. Patients with familial major depressive disorders have been shown to have increased CBF in the amygdala, left medial and LOPFC and extending to the VLPFC.16 Failure to treat depression has been shown to have a deleterious effect on the health of neurons in the hippocampus. The longer a patient with MDD remains untreated, the greater the loss of hippocampal volume as found in a study that measured MRIs in female patients over time.17

Several areas of increased CBF are associated with pain including the insular cortex, amygdala, anterior cingular cortex, thalamus and DLPFC.18 Patients experiencing chronic back pain (CBP) have demonstrated increased activity in the rostral anterior cingulate cortex, the medial prefrontal cortex, amygdala and insular cortex. The degree of activation of the medial prefrontal cortex has been correlated with the intensity of CBP.19

Structural changes in the brain are not limited to depression. Patients with chronic back pain have demonstrated reductions in the volume of the DLPFC and right anterior thalamus. Patients with CBP have been shown to have 5-11% less neocortical grey matter than controls, which was similar to 10 to 20 years of aging of normal controls. The decrease in gray matter volume correlated with duration of CBP indicating a 1cc loss of gray matter for every year of CBP.20 Loss of gray matter has also been demonstrated in fourteen female pain patients versus twenty-five healthy controls. The pain patients had significant losses in gray matter in the rostral and anterior cingulate cortex, VMPFC and anterior insular cortex.21

The “weak link” in the theory of the neurobiology of pain and depression may be the hippocampus. Both serotonin and norepinephrine influence the balance between the excitatory and inhibitory activities in the limbic system and prefrontal cortex.22 Excitatory glutamatergic projections emanate from the prefrontal cortex to the brainstem noradrenergic nuclei (locus ceruleus) and serotonergic nuclei (dorsal raphe). An excessive amount of excitatory input from the VMPFC, combined with increased level of glucocorticoids, may have a toxic effect on hippocampal neurons possibly leading to hippocampal atrophy.23 This may contribute to the cognitive and emotional impairment and neuroendocrine dysregulation associated with MDD.


Neurotrophins are well known for their effects on neuronal growth and survival. The neurotrophins most commonly associated with pain and depression are:

Last updated on: December 27, 2011
First published on: September 1, 2010