Bernadette Demuri, MD

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Patients who have chronic pain and those with a major depressive disorder (MDD) share clinical features, including fatigue, cognitive complaints, and functional limitation. Sleep disturbance and anxiety are common with both disorders. Because pain and depression share common neurobiological pathways (see Part 1 of this article in the February 2016 issue and at CurrentPsychiatry.com) and clinical manifestations, you can use similar strategies and, often, the same agents to treat both conditions when they occur together (Table 1).

What are the medical options?
Antidepressants. Using an antidepressant to treat chronic pain is a common practice in primary care and specialty practice. Antidepressants that modulate multiple neurotransmitters appear to be more efficacious than those with a single mechanism of action.¹ Convergent evidence from preclinical and clinical studies supports the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) as more effective analgesic agents, compared with the mostly noradrenergic antidepressants, which, in turn, are more effective than selective serotonin reuptake inhibitors (SSRIs).² The mechanism of the analgesic action of antidepressants appears to rely on their inhibitory effects of norepinephrine and serotonin reuptake, thereby elevating the performance of endogenous descending pain regulatory pathways.³

Tricyclic antidepressants (TCAs), primarily amitriptyline, nortriptyline, and desipramine, have the advantage of years of clinical experience and low cost. Their side effect burden, however, is higher, especially in geriatric patients. Dose-dependent side effects include sedation, constipation, dry mouth, urinary retention, and orthostatic hypotension.

TCAs must be used with caution in patients with suicidal ideation because of the risk of a potentially lethal intentional overdose.

The key to using a TCA is to start with a low dosage, followed by slow titration. Typically, the dosages of TCAs used in clinical trials that focused on pain have been lower (25 to 100 mg/d of amitriptyline or equivalent) than the dosage typically necessary for treating depression; however, some experts have found that titrating TCAs to higher dosages with an option of monitoring serum levels may benefit some patients.⁴

SNRIs are considered first-line agents for both neuropathic pain and fibromyalgia. Duloxetine has been shown to be effective in both conditions⁵; venlafaxine also has shown efficacy in neuropathic pain.⁶ Milnacipran, another SNRI that blocks 5-HT, and norepinephrine equally and exerts a mild N-methyl-D-aspartate inhibition, has proven efficacy in fibromyalgia.^7,8

SSRIs for alleviating central pain or neuropathic pain are supported by minimal evidence only.⁹ A review of the effectiveness of various antidepressants on pain in diabetic neuropathy concluded that fluoxetine was no more effective than placebo.^10,11 Schreiber and Pick¹¹ evaluated the antinociceptive properties of several SSRIs and offered the opinion that fluoxetine, fluvoxamine, and citalopram were, at best, weak antinociceptors.

Opioids. Data on the long-term benefits of opioids are limited, except for use in carefully selected patients; in any case, risk of abuse, diversion, and even death with these agents is quite high.¹² Also, there is evidence that opioid-induced hyperalgesia might limit the usefulness of opioids for controlling chronic pain.¹³

Gabapentin and pregabalin, both anticonvulsants, act by binding to the α-2-σ subunit of voltage-gated calcium channels within the CNS.¹⁴ By reducing calcium influx at nerve terminals, the drugs diminish the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. This mechanism is thought to be the basis for the analgesic, anticonvulsant, and anxiolytic effects of these drugs.¹⁵

Gabapentin and pregabalin have been shown to decrease pain intensity and improve quality of life and function in patients with neuropathic pain conditions. Pregabalin also has shown efficacy in treating central neuropathic pain and fibromyalgia.¹⁶

Added benefits of these drugs is that they have (1) a better side effect profile than TCAs and (2) fewer drug interactions when they are used as a component of combination therapy. Pregabalin has the additional advantage of less-frequent dosing, linear pharmacokinetics, and a predictable dose-response relationship.¹⁷

Addressing other comorbid psychiatric conditions
Sleep disturbance is common among patients with chronic pain. Sleep deprivation causes a hyperexcitable state that amplifies the pain response.¹⁸

When a patient presents with chronic pain, depression, and disturbed sleep, consider using a sedating antidepressant, such as a TCA. Alternatively, gabapentin or pregabalin can be added to an SNRI; anticonvulsants have been shown to improve quality of sleep.¹⁹ Cognitive-behavioral interventions targeting sleep disturbance may be a helpful adjunct in these patients.²⁰

When anxiety is comorbid with chronic pain, antidepressants with proven efficacy in treating anxiety disorders, such as duloxetine or venlafaxine, can be used. When chronic pain coexists with a specific anxiety disorder (social anxiety disorder, obsessive-compulsive disorder, panic disorder), an SSRI might be more advantageous than an SNRI,²¹ especially if it is combined with a more efficacious analgesic.

Benzodiazepines should be avoided as a routine treatment for comorbid anxiety and pain, because these agents can produce sedation and cognitive interference, and carry the potential for dependence.

Fatigue. In patients who, in addition to pain and depression, complain of fatigue, an activating agent such as milnacipran or adjunct bupropion might be preferable to other agents. Modafinil has been shown to be a well-tolerated and potentially effective augmenting agent for antidepressants when fatigue and sleepiness are present as residual symptoms²²; consider them as adjuncts when managing patients who have chronic pain and depression that manifests as excessive sleepiness and/or fatigue.

Cognitive complaints. We have noted that disturbances of cognition are common in patients with depression and chronic pain, and that cognitive dysfunction might improve after antidepressant treatment.

Studies suggest that SSRIs, duloxetine, and other antidepressants, such as bupropion, might exert a positive effect on learning, memory, and executive function in depressed patients.²³ Beneficial effects of antidepressants may be “pseudo-specific,” however—that is, predominantly a reflection of overall improvement in mood, not on specific amelioration of the cognitive disturbance.

Vortioxetine has shown promise in improving cognitive function in adults with MDD; its cognitive benefits are largely independent of its antidepressant effect.²⁴ The utility of vortioxetine in chronic pain patients has not been studied, but its positive impact on mood, anxiety, sleep, and cognition might make it a consideration for patients with comorbid depression—although it is uncertain at this time whether putative noradrenergic activity makes it suitable for use in chronic pain disorders.

Last, avoid TCAs in patients who have cognitive complaints. These agents have anticholinergic effects that can have an adverse impact on cognitive function.

Cautions: Drug−drug interactions, suicide risk, disrupted sleep
Avoiding drug−drug interactions is an important consideration when treating comorbid disorders. Many chronic pain patients take over-the-counter or prescribed nonsteroidal anti-inflammatory drugs for analgesia; these agents can increase the risk of gastrointestinal bleeding when they are combined with an SSRI or an SNRI.

The use of the opioid tramadol with an SNRI or a TCA is discouraged because of the risk of serotonin syndrome.

Combining a sedating antidepressant, such as a TCA, with gabapentin or pregabalin can increase the risk of CNS depression and psychomotor impairment, especially in geriatric patients. An opioid analgesic is likely to amplify these effects.

Suicidal ideation is not uncommon in patients with chronic pain and depression. To minimize the risk of suicide in patients with a chronic pain disorder, you should ensure optimal pain control by combining the most efficacious analgesic agent with psychotherapeutic interventions and optimal antidepressant treatment. Furthermore, cognitive-behavioral therapy (CBT) (see the discussion below) might not only improve pain coping skills, but also ameliorate catastrophizing, anxiety, and concomitant sleep disturbance.

Complaints of sleep disturbance and anxiety can compound the risk of suicide in a chronic pain patient. When possible, these complex patients should be treated by a multidisciplinary team that includes a pain management specialist, psychotherapist, and primary care clinician. It is important to strengthen the clinician−patient relationship to facilitate close monitoring of symptoms and to provide a trusting environment in which patients feel free to discuss thoughts of suicide or self-harm. For such patients, prescribing opiates and TCAs in small quantities is a prudent action.

When a patient struggles with suicidal thoughts, his (her) family might need to dispense these medications. Most important, if a patient is actively suicidal, consider referral to an inpatient facility or intensive outpatient program, where aggressive treatment of depressive symptoms and intensive monitoring and support can be provided.²⁵

Usefulness of non-drug interventions
There is, of course, a diversity of non-drug treatments for MDD and for chronic pain; discussion here focuses primarily on modalities with established efficacy in both disease states (Table 2). On rare occasions, non-drug treatments can constitute a stand-alone approach; most often, they are incorporated into a multimodal treatment plan or applied as an adjunct intervention.²⁶

Psychotherapy. The most robust evidence supports the use of CBT in addressing MDD and chronic pain—occurring individually and comorbidly.^26-28 Efficacy is well established in MDD, as monotherapy and adjunct treatment, spanning acute and maintenance phases.

Furthermore, CBT also has support from randomized trials, meta-analyses, and treatment guidelines, either as monotherapy or co-therapy for both short-term relief and long-term pain reduction. Additionally, CBT has demonstrated value for relieving pain-related disability.^26,28

Combination of a special form of CBT, rumination-focused CBT with ongoing pharmacological therapy over a 26-week period in a group of medication-refractory MDD patients produced a remission rate of 62%, compared with 21% in a treatment-as-usual group.²⁹ This is of particular interest in chronic pain patients, because rumination-related phenomena of pain catastrophizing and avoidance facilitate a transition from acute to chronic pain, while augmenting pain severity and associated disability.³⁰

Catastrophizing also has been implicated in mediating the relationship between pain and sleep disturbance. Not surprisingly, a randomized controlled study demonstrated the benefit of 8-week, Internet-delivered CBT in patients suffering from comorbid chronic pain, depression, and anxiety. Treatment significantly diminished pain catastrophizing, depression, and anxiety; maintenance of improvement was demonstrated after 1 year of follow-up.³¹

Other behavioral and psychological approaches. Biofeedback, mindfulness-based stress reduction, relaxation training and diaphragmatic breathing, guided imagery, hypnosis, and supportive groups might play an important role as components of an integrated mind−body approach to chronic pain,^28,32,33 while also providing mood benefits.

Exercise. The role of exercise as a primary treatment of MDD continues to be controversial, but its benefits as an add-on intervention are indisputable. Exercise not only complements pharmacotherapy to produce greater reduction in depressive scores and improvement in quality of life, it might aid in reestablishing social contacts when conducted in a group setting—an effect that can be of great value in both MDD and chronic pain.³⁴

Exercise and restorative therapies provide several benefits for chronic pain patients, including:

• improved pain control, cognition, and mood
• greater strength and endurance
• cardiovascular and metabolic benefits
• improved bone health and functionality.^{26,28,32,33,35}

To achieve optimal benefit, an exercise program must be customized to fit the patient’s physical condition, level of fitness, and specific type of pain.³⁵ Preliminary evidence suggests that, beyond improvement in pain and functionality, exercise might reduce depressive symptoms in chronic pain patients.³⁶

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

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 (Box^35-37).

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

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

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 (Box^35-37).

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

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.

Any discussion of the relationship between major depressive disorder (MDD) and chronic pain encounters an obstacle immediately: Neither has a singular pathophysiology. Furthermore, MDD and, to a significant extent, chronic pain are defined more by their symptoms than by a presumed etiology and pathogenesis.

Why does this matter to a busy clinician?
Explicitly or implicitly, we often align our treatment approaches with what we assume is the underlying pathophysiology of the conditions we are addressing. An overview of shared pathophysiology of chronic pain conditions and MDD therefore can be useful in practice.

What is chronic pain? Defined as “pain that persists past the healing phase following an injury,”¹ chronic pain often is subdivided into 4 types^2,3:

• nociceptive (caused by a lesion or potential tissue damage)
• inflammatory
• neuropathic (spontaneous pain or hypersensitivity to pain related to neurologic illness or injury)
• functional (hypersensitivity to pain due to abnormal central processing of a normal input).

Although fibromyalgia often is categorized as a dysfunctional pain syndrome, persons who suffer from it, much like those who suffer neuropathic pain, commonly report hyperalgesia (augmented sensitivity to painful stimuli), allodynia (abnormal pain response to non-noxious stimuli), and paresthesias. These shared clinical features of fibromyalgia and neuropathic pain are consistent with central sensitization, which suggests overlapping pathophysiology.⁴

Comorbidity between depression and pain is common. A 30% to 60% co-occurrence rate of MDD and chronic pain has been reported.⁵ Some subtypes of chronic pain, such as fibromyalgia, are so commonly comorbid with psychiatric conditions that they have spawned a scientific debate as to whether the conditions are most parsimoniously considered (1) separate illnesses with high comorbidity or (2) different symptomatic manifestations of a single underlying condition.⁶ Moreover, cumulative evidence suggests that chronic pain and depression do not just co-occur; each one facilitates development of the other, such that chronic pain is a strong predictor of subsequent onset of MDD, and vice versa.

When pain and depression are comorbid, they also tend to make treatment of each condition more difficult. For example, pain presents (1) a major obstacle to achieving remission when treating depression^7,8 and (2) significant risk of relapse.⁹ A 3-year longitudinal study showed that painful symptoms substantially reduced the chance of recovery in a group of older depressed patients (n = 327). A substantially greater percentage of patients with MDD alone attained recovery (47%), compared with only 9% in whom MDD and painful symptoms were comorbid.¹⁰ Furthermore, a higher level of pain can delay remission when treating MDD,¹¹ thus reducing the likelihood of an optimal outcome.¹²

Understanding shared processes. Recent developments in neuroscience and psycho-immunology point to the fact that comorbid pain and depression might be driven by overlapping pathophysiological processes in the brain and body. In the 2 parts of this article, we (1) review scientific understanding of these shared processes and (2) demonstrate how recent advances in the epidemiology, phenomenology, and etiology of chronic pain and MDD provide important clues for more effective diagnosis (Part 1) and treatment (Part 2, March 2016)—and, therefore, better outcomes. Our focus is primarily on the relationship between MDD and the best-studied comorbid chronic pain conditions: fibromyalgia, neuropathic pain, chronic back pain, and rheumatoid arthritis.

The societal burden of chronic pain conditions is enormous
A recent epidemiological study¹³ projected that as many as 100 million people in the United States—30.7% of the population—suffer some form of chronic pain, including arthritis and joint pain. A World Health Organization survey yielded a similar (and staggering) 37% prevalence of chronic pain in the population of 10 developed countries.¹⁴

Estimates are that various forms of neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, spinal cord injury, and radiculopathy, alone afflict as many as 26 million people worldwide, including approximately 1.5% of the U.S. population.^15,16

Chronic low back pain is epidemic. With a projected point prevalence of 30%, the condition is the most common cause of activity limitation among people age <45, and the most frequent reason in the United States for visiting a physician.¹

Functional somatic syndromes, including fibromyalgia and irritable bowel syndrome, impose an astounding strain on health care: These syndromes account for 25% to 50% of all outpatient visits, or approximately 400 million clinic visits annually in the United States.¹⁷

Why should you care about these numbers? The answer is that comorbidity among chronic pain, mood disorders, anxiety disorders, sleep disorders, cognitive impairment, fatigue, and chronic stress presents an enormous clinical challenge because it not only complicates the diagnosis of these conditions but also compromises treatment outcomes and imposes severe limitations on daily functioning and quality of life of those afflicted.^5,17-24

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 (Box^35-37).

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

Likewise, the mPFC is a key component of the default mode network (DMN), a functional network also comprising the posterior cingulate cortex and hippocampus. DMN performs a diverse set of activities, including self-reflection, daydreaming, reminiscing, planning, processing of social information, and creative thinking. Negative neuroplastic changes in the DMN are a common finding in MDD and chronic pain, and might be associated with a tendency toward rumination and catastrophizing—key clinical manifestations of MDD and chronic pain—and linked with pervasive negative affect and sleep disturbance.^4,32

Furthermore, functional and structural changes in the amygdala and hippocampus have been described in MDD, fibromyalgia, and neuropathic pain.⁴ Dysfunction of these limbic formations may be a contributing factor in the disruption of neuroendocrine, autonomic, and immune function, which could further contribute to aggravated mood and pain symptoms.^4,17,40

Consequently, excessive hypothalamic-pituitary-adrenal axis and sympathetic activation, combined with elevation of proinflammatory cytokine production and release, likely plays a role in the pathophysiology of MDD and chronic pain disorders.^4,17,40 Moreover, at cellular, subcellular, and molecular levels, chronic pain and MDD are associated with:

• perturbed neuron-glia relationships
• altered glutamatergic, GABA, glycine, substance-P, opioid, 5-HT, norepinephrine, and dopamine signaling
• dysfunction of intracellular signaling cascades and neurotrophic signaling.^{4,20,30,31,38}

The Figure that describes how homeostatic function of prefrontal cortical-limbic circuitry is compromised in MDD and chronic pain—thus disrupting autonomic, neuroendocrine, and neuroimmune regulation.

Disturbance in monoamine signaling in chronic pain and MDD might give rise to profound anhedonia, cognitive impairment, anxiety, insomnia, sensitivity to stress, and inadequate functioning of descending pain-regulatory pathways, which primarily use norepinephrine and 5-HT.^{4,9,20,30,31,38} Using pharmacotherapeutic agents that successfully modulate monoamines, therefore, might ameliorate the function of brain networks innervated by neurotransmitter systems involved in the regulation of pain, mood, cognition, stress response, and sleep. Notably, the same monoamines serve as transmitters in descending pain pathways.

In summary, convergent evidence indicates that MDD and chronic pain states amplify each other, thus contributing to treatment resistance in both disorders.

On the bright side, timely and effective treatment of MDD might optimize the chance of remission and minimize the risk of enduring structural brain changes in MDD and chronic pain.^1,4,31,32 The obverse is also true: Emphasizing the importance of the resolution of painful symptoms in the context of MDD, a study reported a significantly greater remission rate of 36.2% in those who had >50% reduction of pain on a visual analogue scale following treatment with a serotonin-norepinephrine reuptake inhibitor, compared with a 17.8% remission rate in persons who experienced <50% pain reduction on the scale.³

Editors’ note: In Part 2 of this article (March 2016), the authors review pharmacotherapeutic and non-drug strategies for managing comorbid chronic pain conditions and MDD.