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11 Articles in Volume 10, Issue #7
Selecting an Antidepressant for Pain Patients
Use of Opioids in Pain Patients with Psychiatric Disorders
Osteopathic Medicine Approach to Pain Management
Cannabis as Medicine
Pain Management in Patients with Pyoderma Gangrenosum
Occipito-Atlanto (C0-C1) Joints as a Source of Spinal Pain
Treat the Pain First—Worry about Psyche Problems Later
Traditional Chinese Medicine for Fibromyalgia
TMJ Condylar Pain From Parapharyngeal Space Tumor
Contraindications for Use of Therapeutic Laser
Platelet-Rich Plasma Prolotherapy for Low Back Pain Caused by Sacroiliac Joint Laxity

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.

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:

  • nerve growth factor (NGF)
  • brain derived neurotrophic factor (BDNF)
  • neurotensin-3 (NT-3)
  • neurotensin 4/5 (NT4/5)

NGF is a peripheral pain mediator and NT-3 and NT4/5 are mainly involved in the development of mechanoceptors and are of lesser importance in nociception. BDNF expression is regulated by NGF and the pro-form may facilitate some pain pathways.24

Neurogenesis, the birth of new neurons, continues post-natally into adulthood and their growth and development is regulated by BDNF.25 BDNF is associated with the regulation of both mood and pain. BDNF is down-regulated in MDD and chronic stress but levels may be increased with successful antidepressant treatment.26 In addition, the neurotransmitters norepinephrine and serotonin are both involved in the expression of BDNF.25

In animal models of both acute and chronic stress and acute and chronic pain, hippocampal BDNF synthesis was significantly decreased.27 BDNF levels in humans have been shown to be inversely correlated with Hamilton Depression Rating Scale scores. Shimuzu and colleagues showed that serum BDNF levels were 36% lower in untreated depressed patients versus controls, while successfully treated depressed patients’ BDNF levels were 10% higher than control groups.28 A comparative study of serum BDNF levels in patients who were depressed and who attempted suicide showed BDNF to be 32% lower—both in patients with MDD and those who attempted suicide—compared to healthy controls.29

Pain, Depression, Steroids, and Hypothalamic-Pituitary-Adrenal Dysfunction

Patients with MDD have demonstrated significant imbalances in their hypothalamic-pituitary-adrenal axis (HPA axis). Salivary cortisol levels may be correlated with impairment in executive functioning and memory as measured by the Wisconsin Card Sorting Test.30 Corticosterone can cause neuronal loss, hippocampal atrophy and the downregulation of BDNF in rat brain. In one study, corticosterone-reduced BDNF levels were significantly increased by the MAO inhibitor phenel-zine and only partially reversed by the SSRI fluoxetine.31

Interestingly, estrogen has a powerful effect on the growth of neurons in the ventromedial nucleus, hypothalamus and amygdale. Estrogen has been shown to increase BDNF expression in the hippocampus and amygdala in rat brain.32

Treatment Recommendations

Since pain symptoms are common with MDD, it is important for effective treatment of MDD to ameliorate pain symptoms to the greatest degree possible. An analysis of pooled data from two studies revealed that effective treatment of pain symptoms improved the overall remission rate of MDD.33 In almost 500 subjects, those whose pain scores (Visual Analog Scores) improved by 50% or greater had twice the remission rates of those subjects whose pain was not as effectively treated.

Table 1. Dosing of Selective Serotonin Norepinephine
Reuptake Inhibitors (SNRIs)
Agent Dosing Range
Duloxetine (Cymbalta®) 30 – 120mg daily
Venlafaxine (Effexor®) 37.5 – 225mg daily
Milnacipran (Savella®) 5 – 200mg in divided doses
Desmehtylvenlafaxine (Pristiq®) 50 – 100mg daily
Table 2. FDA-Approved Uses of Selective Serotonin
Norepinephrine Reuptake Inhibitors (SNRIs)
Agent MDD* Fibro-myalgia DPNP** GAD*** Social Phobia Panic
Duloxetine (Cymbalta®) x x x x    
Venlafaxine (Effexor®) x       x x
Milnacipran (Savella®)   x        
Desmethylvenlafaxine (Pristiq®) x          
*Major depressive disorder; **Diabetic peripheral neuropathic pain; ***Generalized anxiety disorder

Remission is a key endpoint in the treatment of depression, as mere improvement in depressive symptoms is not enough to ensure a good prognosis. In a study of 183 patients with MDD followed for two years, 87% of those who did not achieve remission of depression relapsed within two years, in contrast to only 16% of patients who achieved remission and relapsed within that same period.34 There are also structural differences in patients with MDD who have remitted versus those who have not achieved remission. In a study of 30 patients with MDD, hippocampal volumes were smaller at one year follow up and at baseline compared to patients who had achieved remission. In addition, the right hippocampal volume of non-remitted patients was smaller compared with matched controls.35

Given the wide spectrum of antidepressants to choose from, the clinician can be overwhelmed by the various classes and mechanisms of actions of the antidepressants. The oldest class of antidepressants used to treat not only mood disorders but also chronic painful conditions are the tricyclic antidepressants (TCAs). TCAs have been effective in the treatment of chronic pain but are limited by their toxicity and adverse effect profile. In addition, doses commonly used to treat painful conditions (e.g., amitriptyline 25-100mg) are inadequate to concurrently treat a patient’s co-morbid mood disorder. The tolerability of TCAs also preclude their use—especially in the geriatric population—due to their cardiotoxicity and strong anticholinergic properties that compromise cognition and voiding in patients with BPH.

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac®), sertraline (Zoloft®), escitalopram (Lexapro®), paroxetine (Paxil®), etc., are all effective in treating various mood and anxiety disorders but have been very disappointing in their ability to treat painful symptoms.36 Agents that inhibit the reuptake of not only serotonin but also norepinephrine—the serotonin norepinephrine reuptake inhibitors (SNRIs)—have demonstrated good analgesic activity, especially in the treatment of neuropathic pain. SNRIs currently on the market are duloxetine (Cymbalta®), desvenlafaxine (Pristiq®) and milnacipran (Savella®). Venlafaxine (Effexor®) is an SSRI whose major metabolite is the SNRI desmethylvenlafaxine which is the currently marketed product Pristiq (see Table 1). In order for venlafaxine to show any antinociceptive activity, doses of the venlafaxine must be high enough to produce enough of the metabolite. Issues of systolic and diastolic hypertension will frequently preclude use at these doses.

The exact explanation for the effectiveness of SNRIs over SSRIs in treating pain is unknown at this time. There is speculation that the antinociceptive effectiveness of SNRIs may involve the suppression of pain impulses by descending spinal tracts from the brain stem synapsing on spinal interneurons. Serotonergic tracts contain both facilitory and inhibitory pathways and are thought to cancel each other out. Descending noradrenergic tracts are thought to be inhibitory, and thus attenuate ascending pain impulses at the spinal level.37

Currently duloxetine (Cymbalta) is approved to treat MDD, generalized anxiety disorder, diabetic peripheral neuropathic pain (DPNP) and fibromyalgia. Desvenlafaxine (Pristiq) is currently approved only for the treatment of MDD. Milnacipran (Savella) is currently approved for the treatment of fibro-myalgia only. Venlafaxine (Effexor) is currently approved to treat MDD, generalized anxiety disorder, panic disorder and social anxiety disorder. Adequate dosing is critical to help insure a good treatment outcome. In our clinical experience, patients with both pain and depression generally require higher doses of SNRIs to achieve maximal results.


Major depressive disorder and pain are highly co-morbid and cause tremendous disruption in both quality of life and functionality. Inadequate treatment of one will most likely result in a poor outcome with the other. Interestingly, there are similar brain regions and pathways associated with both pain and depression. Moreover, untreated depression and pain has been correlated with loss of brain tissue. Neurotrophins such as BDNF are integral in maintaining the health of neurons by facilitating neurogenesis, neuroprotection and neuroplasticity. BDNF becomes depleted in depression, chronic pain and chronic stress but can be increased with treatment by antidepressants. Dysfunction of the HPA axis due to chronic pain, chronic stress and/or MDD can lead to overstimulation of excitatory glutamatergic pathways leading to neurotoxicity and cell death. Restoring neurotrophin levels appears to play a key role in preventing this.

Treatment options for patients with co-morbid pain and depression optimally involve using medications that inhibit the reuptake of both serotonin and norepinephrine (see Table 2). SNRIs such as duloxetine (Cymbalta), milnacipran (Savella), desvenlafaxine (Pristiq) and venlafaxine (Effexor) are proposed to have the ability to inhibit ascending pain impulses at the level of the spinal cord through activation of inhibitory descending tracts from the brain stem. Tricyclic antidepressants (TCAs) have been limited in their usefulness in the treatment of pain and depression due to their toxicity and bothersome adverse event profile. SSRIs have been disappointing in their ability to treat both depression and painful symptoms.

Aggressive treatment of depressive symptoms to the point of remission will make it easier for the clinician treating chronic pain to provide adequate pain control in their patients. Conversely, adequate pain control will also make it easier to achieve remission of depression in patients with MDD.

Last updated on: December 27, 2011
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