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Antidepressants in the Treatment of Chronic Pain

Chronic pain and depression have a shared neurobiology and neuro-anatomy. Recent studies have found that anti-depressants improve pain symptoms regardless of the presence of absence of co-morbid major depression.
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There are 4 points upon which there is broad consensus in the field and that we should discuss immediately:

  • Major depression and chronic pain are common conditions, and they frequently overlap.1,2 (See Figures 1 and 2.)
  • Anti-depressants can improve symptoms of major depression, regardless of the presence or absence of co-morbid pain (though pain can reduce the chances of optimal recovery).3,4
  • Anti-depressants improve pain symptoms regardless of the presence or absence of co-morbid major depression.5-7
  • Chronic pain and major depression have a shared neurobiology and appear to have a shared neuro-anatomy (in the brain and spinal column) and neuro-chemistry (norepinephrine and serotonin), with similar hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system (ANS), and inflammatory cytokine disturbances.8-10

Types of Anti-depressants: A Quick Primer for the Pain Physician

Numerous classes of anti-depressants (ADs) are available for physicians to prescribe. (See Figure 3.) However, it is clear from pre-clinical and clinical data that ADs are not equally efficacious in chronic pain management.11 Broadly speaking, they can be classified into the following categories: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-depressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), monoamine oxidase inhibitors (MAOIs), and atypical anti-depressants (an assortment of ADs with other mechanisms of action). All of these ADs have an important role in treating depression, but in the treatment of patients with chronic pain (with or without depression), 2 classes of anti-depressants stand out—TCAs and SNRIs.11-13

How Do Agents Reduce Pain?

TCAs and SNRIs share the ability to modulate the neurotransmission of both serotonin and norepinephrine. This appears to affect the pain circuitry both at the cerebral and at the spinal column level.14,15 They also appear to modulate the functioning of the dorsolateral prefrontal cortex (DLPFC), insular cortex, amygdala, and hippocampus; as well as the descending pain pathway in the spinal column.16,17 Because these areas of the brain are also affected in patients with major depressive disorders (MDDs), this may be the reason why these ADs have demonstrated efficacy in all 3 scenarios—in major depression alone, in major depression and chronic pain together, or in chronic pain alone.

Link Between Chronic Pain and Depression

In the last decade or so, emerging and persuasive evidence reveals that inflammation plays an important role in the pathogenesis of both clinical depression and chronic pain syndromes.18 The common denominator of inflammation between chronic pain and clinical depression may partly explain why patients with clinical depression are more prone to develop chronic pain and vice versa. This provocative view is now well supported by emerging evidence from both fields of study—depression and chronic pain—and it partly explains why patients with one condition are more prone to develop the other condition.

Stress, anxiety, and depression—all states of heightened arousal—not only provoke emotional distress, but also destabilize the HPA axis.19 Additionally, the ANS is often dysregulated in depression and chronic pain states. Finally, the cell-mediated immune system is also affected, resulting in over-production of inflammatory cytokines and diminished production of anti-inflammatory cytokines.20-22 Interestingly, similar changes also occur in patients with chronic pain. There is good evidence that these changes (HPA axis, ANS, and cytokine deregulation) play an important role in creating clinical depression and destabilizing an individual’s innate pain regulating system.23,24


Anti-depressants as Anti-inflammatory Agents

Recent evidence indicates that ADs act as anti-inflammatory agents in both depression and chronic pain states.25,26 Anti-depressant treatments zimprove the clinical symptoms of depression and chronic pain and appear to positively impact immune/cytokine deregulations. Research data indicate that ADs can reduce levels of inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6.27-29 Other anti-depressant interventions that are non-pharmacological, such as cognitive behavioral therapy and physical exercise, interestingly also show the same positive and salutary effects on the immune/cytokine system.30

These findings raise an interesting question: Should anti-depressant use be limited to only those patients who have both chronic pain and depression? The answer to this question is No! Here’s why:

  • Both animal and pre-clinical data clearly show that anti-depressants (mostly the TCAs and SNRIs) have anti-nociceptive properties.12
  • Multiple studies reveal that even in the absence of depression, these anti-depressants have efficacy in multiple chronic pain conditions irrespective of co-morbid chronic clinical depression.31
  • In the last decade, based on multiple, large, well-conducted studies, many ADs have received US Food and Drug Administration (FDA) indication for various chronic pain conditions, even in the absence of clinical depression.32,33
  • Obviously, the presence of significant and impairing depression in an individual with chronic pain calls for treatment with an AD. But the positive benefits of ADs—even in the absence of clinical depression—are worth keeping in mind.

When to Use for Pain

Physicians are faced with treating patients with multiple types of chronic pain—neuropathic pain, nociceptive pain, fibromyalgia, and mixed pain conditions. In a surprisingly large number of these conditions, we now have good clinical data revealing the effectiveness of anti-depressants (particularly TCAs and SNRIs). Some of the anti-depressants have FDA indications for certain pain conditions. Note this point from clinical trials: ADs have broad efficacy in pain and depression. A well-conducted study with an SNRI in a depressed population with or without co-morbid arthritis demonstrated this point.4

Fibromyalgia: Many anti-depressants have been used in this chronic pain condition. Currently, 2 SNRI anti-depressants have FDA approval in this condition—duloxetine and milnacipran. TCAs, particularly amitriptyline (not FDA-approved for this indication), are often used in clinical practice, and a large database reveals it’s an efficacious intervention.7,35,36

Last updated on: May 23, 2011
First published on: March 1, 2011