Because depression and painful symptoms commonly occur together, we conducted a literature review to determine the prevalence of both conditions and the effects of comorbidity on diagnosis, clinical outcomes, and treatment. The prevalences of pain in depressed cohorts and depression in pain cohorts are higher than when these conditions are individually examined. The presence of pain negatively affects the recognition and treatment of depression. When pain is moderate to severe, impairs function, and/or is refractory to treatment, it is associated with more depressive symptoms and worse depression outcomes (eg, lower quality of life, decreased work function, and increased health care utilization). Similarly, depression in patients with pain is associated with more pain complaints and greater impairment. Depression and pain share biological pathways and neurotransmitters, which has implications for the treatment of both concurrently. A model that incorporates assessment and treatment of depression and pain simultaneously is necessary for improved outcomes.
Individually, depression and pain symptoms are highly prevalent conditions encountered by primary care physicians and specialists. Epidemiologic studies indicate that the lifetime prevalence of pain symptoms (eg, joint pain, back pain, headache, chest pain, arm or leg pain, and abdominal pain) ranges from 24% to 37%1 and that physical symptoms such as pain are the leading reason that patients seek medical care.2,3 Major depression is also common, with prevalence in primary care patients of 5% to 10%.4 This underestimates the true impact of depression, since many more people have depressive symptoms but do not fully meet the major depressive disorder diagnostic criteria of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition for duration or number of symptoms. Depression has become the fourth leading cause of disability worldwide and is projected to become even more burdensome in the future.5
A growing body of literature has focused on the interaction between depression and pain symptoms. This interaction has been labeled by some authors as the depression-pain syndrome6 or depression-pain dyad, implying that the conditions often coexist, respond to similar treatments, exacerbate one another, and share biological pathways and neurotransmitters.7,8 Patients with depression often present with a complex set of overlapping symptoms, including emotional and physical complaints. Physical complaints typically include medically unexplained pain.9 Although it is generally understood that depression and painful symptoms are common comorbidities and that their combination is costlier and more disabling than either condition alone, their interaction is not fully understood. Understanding this relationship has become more important, given that primary care physicians fail to accurately diagnose at least 50% of patients with major depression,10 and at least 2 studies have shown that patients with depression who present with physical symptoms such as pain are particularly likely to receive an inaccurate diagnosis.11,12 Patients with depression have significantly more unexplained physical symptoms such as pain and fatigue and utilize more health resources than nondepressed patients. The new emphasis on pain as the fifth vital sign by the Joint Commission on Accreditation of Healthcare Organizations and the Veterans Health Administration highlights the importance of a better understanding of the likely reciprocal links between depression and pain.
The present review addresses the following 6 questions: (1) What is the prevalence of pain symptoms in patients with depression and, conversely, what is the prevalence of depression in patients with pain complaints? (2) Does the presence of pain affect provider recognition and treatment of depression? (3) Does the presence of pain affect depression outcomes such as functional limitations, quality of life, health care costs and utilization, and treatment efficacy? (4) Does the presence of depression affect these same clinical outcomes in patients treated for pain? (5) Is antidepressant treatment for painful symptoms and comorbid depression effective? and (6) What are the common biological pathways and implications for treatment choice when depression and pain coexist?
We searched the MEDLINE database from 1966 through July 30, 2002, using the combined search terms depression or depressive disorders and pain. Articles were also identified by a manual search of bibliographies from all retrieved articles. Studies were limited to human studies reported in English. A few abstracts, studies not published in full, and book chapters were included. Two of us (M.J.B. and K.K.) independently screened titles and abstracts and reached agreement on which articles to retrieve. All primary and review articles were examined for information pertinent to our questions.
Studies were eligible for inclusion if they addressed both depression and pain symptoms. Specific symptoms (eg, headache, back pain, neck pain, extremity/joint pain, chest pain, pelvic pain, abdominal pain, and others) as well as general pain (ie, studies that used pain measures but did not specify pain location) were included in the analysis. Articles were included if they had primary data derived from clinical trials or longitudinal or cross-sectional studies. Excluded studies were those addressing pain due to specific disease processes (eg, peripheral neuropathy, rheumatoid arthritis, or cancer pain) or symptom syndromes (eg, fibromyalgia, irritable bowel syndrome, or migraine headache) because these conditions have been the subject of previous reviews.13-20
Because of the broad scope of depression and painful symptoms, the variety of measures used to assess depression, and the different study definitions of pain, formal meta-analytic methods were precluded. Instead, this review is a qualitative and semiquantitative synthesis of the relevant, representative, and evidence-based literature.
What is the prevalence of pain symptoms in patients with depression?
To address the prevalence of depression and pain symptoms, we summarized the literature based on whether the subjects presented with depression and were then assessed for pain (14 articles) or if patients with a painful condition were assessed for depression (42 articles). Fourteen studies6,21-33 were identified that focused on the prevalence of pain symptoms in patients with depression (Table 1). The prevalence of pain ranged from 15% to 100% (mean prevalence, 65%). Most of the studies were uncontrolled and performed in psychiatric settings. Only 3 studies6,24,29 examined primary care patients, and 2 studies solicited community volunteers.25,32 The prevalence rates do not appear to be influenced by the study setting in that there does not seem to be a different prevalence in psychiatric vs primary care settings. Sample sizes were modest, ranging from 16 to 573 patients (mean, 137). Pain was primarily assessed at the clinical interview or self-assessed by the patient presenting with the pain complaint. The definition of pain condition, location of pain, and duration of pain complaint varied considerably among studies. Several different scales were used to assess depression.
A large longitudinal cohort study has shown that depressive symptoms predict future episodes of low back pain, neck-shoulder pain, and musculoskeletal symptoms compared with those patients without depressive symptoms at baseline.34 Another study showed that low back pain is more than 2 times as likely to be reported by individuals with depressive symptoms compared with those without depressive symptoms.35 In addition, the specific complaints of headache, abdominal pain, joint pain, and chest pain are frequently reported by patients with depression in primary care settings25,36 and by elderly nursing home residents.37
What is the prevalence of major depression in pain patients?
Several reviews38-42 have examined the prevalence of major depression in patients with pain. Table 2 summarizes 42 studies6,36,43-82 identified by our literature search. Fifteen studies were from pain clinics or inpatient pain programs; 9 from psychiatric clinics or psychiatric consultation; 3 from arthritis, rheumatology, or orthopedic clinics (excluding rheumatoid arthritis and fibromyalgia studies); 3 from dental/facial pain clinics; 2 from surgical patients; and 10 from primary care or population-based settings. Most studies (n = 31) focused on "chronic" pain complaints of at least 6 months' duration.
The mean (range) prevalence rates for concurrent major depression in patients identified as having pain by study setting are as follows: 52% (1.5%-100%) in pain clinics or inpatient pain programs; 38% (6%-64%) in psychiatric clinics or psychiatric consultation; 56% (21%-89%) in orthopedic clinics or rheumatology clinics (excluding studies focusing on fibromyalgia or rheumatoid arthritis); 85% (35%-100%) in dental clinics addressing facial pain; 13% (12%-17%) in gynecology clinics addressing chronic pelvic pain in laparoscopy patients; 18% (4.7%-22%) in population-based settings; and 27% (5.9%-46%) in primary care clinics. In addition to the point prevalence rates listed in Table 2, two studies54,73 also reported the lifetime prevalence of major depression in pain patients. Rates of depression increased from 12% to 32%73 and 32.4% to 56.8%,54 respectively. When the etiology of the pain condition is considered, studies of more defined pain disorders (eg, peripheral neuropathy) report lower occurrence of depression than studies of medically unexplained pain.61
A variety of instruments were used to diagnose depression, including the Beck Depression Inventory, Center for Epidemiological Studies Depression Scale, Primary Care Evaluation for Mental Disorders, Geriatric Depression Scale, Feighner criteria, and Hopkins Symptom Checklist. Pain was assessed mainly through clinical interview or different pain questionnaires. The substantial variation in prevalence rates is likely related to differences in diagnostic criteria used for depression, pain conditions examined, study designs, and subject populations.
Several studies have reported the association between depression and pain, specifically addressing how the risk of depression increases as a function of different aspects of worsening pain (eg, severity, frequency, duration, and number of symptoms). Patients with multiple pain symptoms (eg, back pain, headache, abdominal pain, chest pain, and facial pain) are 3 to 5 times more likely to be depressed than patients without pain,81 and pain symptoms are associated with at least a 2-fold increased risk for coexisting depression.83 Additionally, a population-based study showed that subjects with chronic pain (defined as pain for most days for at least a month) are 3 times as likely to meet depression criteria as those without chronic pain.80 The association between depression and pain becomes stronger as the severity of either condition increases. For example, as the severity of pain increases, depressive symptoms and depression diagnoses become more prevalent.75,77,84 Likewise, as depression symptoms increase in severity, pain complaints are reported more often.81
Consistent with findings in primary care patients,36 multiple pain complaints increase the probability of depression38 such that patients with 2 or more different pain complaints are 6 times more likely to be depressed, and patients with 3 or more pain complaints are 8 times more likely to meet depression criteria.10 In addition, more frequent pain episodes85 and longer pain duration are associated with depression. An international study showed that patients with pain lasting longer than 6 months were more than 4 times as likely to have a depressive disorder as those without chronic pain.86 The long-term medical conditions most strongly associated longitudinally with the development of incident depression included back pain and migraine headaches.87
Does the presence of pain affect provider recognition and treatment of depression?
Fourteen studies sought to determine whether the presence of pain affected provider recognition of depression. In depression studies not addressing pain, at least half of patients with major depression were not properly diagnosed and therefore not treated for depression in primary care settings.11,88 Although many factors account for this problem, the most important reason relates to how the patient presents. The "typical" depression presentation in primary care is dominated by physical (somatic) complaints as opposed to psychological complaints. More than 50% of patients with depression report somatic complaints only11,12,24,89-92 and at least 60% of these somatic complaints are pain related.24,25,36,93 Thus, patients with depression in primary care settings are more likely to report various pain symptoms than they are to present with dysphoric mood or anhedonia. Physical (or somatic) symptoms of depression, specifically fatigue, insomnia, and pain complaints, are more numerous in patients with depression, are frequently nonspecific,91,94 and are often unrelated to a known organic disease process.3
The patient's presentation of physical complaints (and the prominence of pain symptoms) interferes with the recognition of depression for patients in primary care settings. Presentation of progressively more physical complaints reduces depression recognition11,12 because patients and their medical providers (at least initially) often associate these symptoms with an underlying medical illness instead of an underlying depressive disorder. Previous work has shown that if all primary care patients presenting with a variety of pain conditions (eg, abdominal pain, headache, joint pain, and back pain) were evaluated for possible depression, 60% of previously undetected depression cases could have been recognized.95 Patients having multiple presenting physical complaints, including nonspecific musculoskeletal complaints and back pain, had more underlying depressive symptoms.96 Additionally, patients presenting with somatic complaints are more likely to have subclinical and milder cases of depression that negatively affect recognition: milder cases of depression are more difficult to detect than more severe and blatant cases, and patients with milder cases are more likely to present to primary care providers than to psychiatrists.
Few studies focused on how pain plays a role in depression treatment considerations. For example, patients often attribute their painful physical symptoms to an underlying medical illness and want treatment for their pain. Health care providers frequently accept the patient's request for pain treatment, while neglecting treatment for the patient's underlying depression. Fritzsche et al97 noticed that patients with depression and pain who lacked psychological attribution to their illness were offered less psychosocial treatment, experienced worse outcomes, and received more medications and physical therapy.
Only older studies addressed how specific medication practices were influenced by pain in patients with depression. For example, opioid analgesics were more commonly prescribed than antidepressants in a sample of patients with depression and chronic pain,98 and there were no differences in sedative and antidepressant medications used in chronic pain patients with and without depression.48 As a result, patients with chronic pain are at risk for polypharmacy, adverse drug events, and narcotic and/or benzodiazepine dependence or addiction.99,100
Does the presence of pain affect depression outcomes?
Outcomes included depression severity and secondary measures such as functional status, quality of life, health care costs and utilization, and treatment efficacy. Unfortunately, most depression and pain studies have either been cross-sectional or have assessed the prognostic value of depression for poor pain outcomes. Relatively few studies have specifically addressed how the presence of pain affects depression outcomes. Most work in this area has been performed by Von Korff et al81 showing that the presence of up to 5 different pain complaints (abdominal pain, headache, back pain, chest pain, and facial pain) is associated with increased symptoms of depression. Further study demonstrated that progressive pain severity at baseline was associated with poor depression outcomes, including more severe depression, more pain-related functional limitations, worse self-rated health, higher unemployment rate, more frequent use of opioid analgesics, and more frequent pain-related doctor visits (at baseline and 1-year follow-up).101 Interference with daily activities due to pain, the number of days in pain (within a 6-month period), and the diffuseness of pain (or number of pain sites) also predicted the severity of depression.102 Unimproved back pain at short-term (7-week) and long-term (2-year) follow-up was associated with significantly more depressive symptoms and chronic depression when compared with patients whose back pain improved.101,103,104 Over the long term, improvement in pain symptoms was associated with a decrease in depressive symptoms to nearly normal.81
When evaluated by changes in physical symptoms, psychiatric symptoms, and functional outcomes, patients without painful physical symptoms were found to have better depression outcomes.105 In a sample of 217 patients with depression, pain was experienced on more than half the days over a 3-month period, producing 16 days when usual activities were curtailed, 4 days missed from school or work, and at least 1 visit with a physician or clinical nurse.106 Retrospective studies suggest that patients with depression have significantly more clinic visits, phone calls to the clinic, and hospitalizations for pain-related symptoms in the months leading up to a diagnosis of depression.107,108 A population-based study found that persons with depression and concomitant pain initiated 20% more visits to medical providers and their total medical costs were higher than persons with depression but without pain.109 Although some studies suggest that patients with depression and comorbid chronic low back pain respond just as well (eg, fewer depression symptoms) to antidepressants and cognitive behavioral therapy as depressed patients without back pain, little is known about how or if pain complicates depression outcomes.110,111 Bair et al21 suggest that baseline pain reduces the benefits of antidepressant therapy at 12 weeks in terms of depression and other quality-of-life outcomes, but more prospective studies are needed to better quantify this.
The goal of depression treatment is complete symptom resolution or remission. Lingering physical symptoms in patients with depression may prevent patients from achieving remission of their depression. Currently, up to 70% of patients respond to treatment but fail to achieve complete resolution of their emotional and physical symptoms.112,113 A recent clinical study114 found that 76% of compliant depressed patients with lingering symptoms of depression relapsed within 10 months. Of these patients who experienced lingering symptoms, 94% had mild to moderate physical complaints.114
Does the presence of depression affect clinical outcomes in patients treated for pain?
We identified 22 studies34,35,55,67,76,77,82,89,103,115-127 that addressed how depression or depressive symptoms affect outcomes in patients with pain (Table 3). Ten of the studies were based in managed care or other primary care settings, 6 in pain and/or specialty clinics, 4 were population-based, 1 study was conducted at a worksite, and 1 in surgical patients. The most common pain condition examined was low back pain. Depression was associated with an array of poor pain outcomes and worse prognosis. Patients with pain and comorbid depression experienced more pain complaints,89 more intense pain,77 more amplification of pain symptoms,82 and longer duration of pain.116 Unfortunately patients with both conditions were more likely to have persistent pain116,120,123,125 and nonrecovery.120 Future episodes of pain, such as low back pain, chest pain, headache, and musculoskeletal complaints were predicted by the presence of depression.34,35,124,127
Functional limitations (eg, limited mobility, activity restrictions) and resulting disability, such as days in bed ill and hospitalizations, were increased in patients with pain and depression.77,82,89,116,117 Similarly, depression and pain produced additive impairments in social functioning,76,82 higher unemployment rates,42,55,67,118 and diminished patient satisfaction.103 Engel et al119 showed that increased depressive symptoms in patients with low back pain also increased health care utilization. Higher depressive symptoms were associated with more primary care follow-up visits for back pain, more back pain–related radiographs, more pain medication refills, and higher total costs.89 "Poor outcomes" were observed at short-term (7 weeks) and long-term (1 year) follow-up.103 In surgical patients, those with higher preoperative depression scores experienced greater postoperative pain.126
Some studies35,116 and a literature review by Linton128 have suggested that depression has a greater impact than other clinical factors on outcomes, especially functional impairment, in patients with pain, and that neglecting to treat the depression accounts for some of the pain treatment failures.38,52 Patients with depression and chronic pain were less likely to comply with pain rehabilitation and thus more likely to relapse following treatment.121,122 Although most studies (Table 3) support the finding that patients with pain and depression have poorer overall response to treatment than pain patients without depression, a few did not report such a relationship.55,121,129,130
Is antidepressant treatment for painful symptoms and comorbid depression effective?
Feinmann131 has previously reviewed studies that reported pain relief associated with depression symptom relief. We identified 22 studies6,71,132-151 that examined antidepressant efficacy for treating pain symptoms and subsequent depression response (Table 4). We did not include studies of symptom syndromes (eg, fibromyalgia, irritable bowel syndrome, migraine headaches) or studies excluding patients with depression or organic pain (eg, diabetic neuropathy, cancer pain) because these conditions have been reviewed previously, and antidepressants were found to be effective.18-20,152,153 The primary outcome in all the studies in Table 4 was pain relief or other pain outcomes, while depression symptom relief was one of the secondary outcomes. Sample sizes were relatively small, ranging from 14 to 253. Only 4 studies6,132,137,141 were conducted in a primary care setting, with the remainder situated in pain, psychiatric, and specialty clinics. The intervention arm of each selected study usually involved tricyclic antidepressants, and only 4 studies involved selective serotonin reuptake inhibitors (SSRIs)135,138,143,145 to assess pain and depression. While most of the studies demonstrated improvement in both pain and depression symptoms, a few of the studies132,142,147 failed to show symptom relief. Whether SSRIs improve painful symptoms associated with depression is unsettled. Most studies were uncontrolled, of short duration (averaging 9 weeks), and used doses that were subtherapeutic for adequate depression treatment.
Anecdotal reports note that when depression is successfully treated, the patient's somatic symptoms, particularly pain complaints, are also relieved.59,88 In a 6-week clinical trial comparing fluoxetine with placebo, outpatients with major depression who were treated with active medication had significant improvements in functional health, including painful symptoms, compared with the placebo group.154 However, a trial investigating a collaborative management program for depression vs usual care showed significantly fewer somatization symptoms at follow-up but no significant intervention effect on pain symptoms.155 A relatively recent meta-analysis153 of antidepressant use in treating symptom syndromes and unexplained symptoms found that symptom improvement did not usually correlate with depression response in the studies where both pain and depression were assessed. Only a third of studies showed improvement in physical symptoms in concert with depression response. Similarly, a review of cognitive-behavioral therapy for somatic symptoms showed an effect on somatic symptoms that appeared, at least in part, independent of an effect on psychological distress.156 Several studies have examined the use of SSRIs in pain syndromes such as diabetic neuropathy and fibromyalgia, but few of these have assessed changes in both pain and depression.157 On the other hand, Ward et al32 reported that the degree of depression improvement correlated with the amount of pain relief. Other studies have suggested that the combination of antidepressants and cognitive behavioral therapy may be effective in treating patients with both chronic pain and depression.6,44,47
What are the common biological pathways for depression and pain, and what are the implications for treatment?
The biochemical theory of depression posits that depression is the result of a neurochemical imbalance or a functional deficiency of key neurotransmitters, the monoamines: serotonin, norepinephrine, and dopamine. A common theory holds that depression and painful symptoms follow the same descending pathways of the central nervous system. Eight studies described the biological link between depression and pain. Although nociceptive fibers transmitting pain signals from the periphery of the body through the dorsal horn to the medulla, midbrain, hypothalamus, thalamus, limbic cortical areas (anterior cingulate and insular cortex), somatosensory cortex, and posterior parietal cortex have been carefully mapped, there is an increasing interest in the neuroanatomy of a descending system of pain modulation.158 The increasing knowledge about this system allows scientists and physicians to better understand mechanisms of pain modulation via medications as well as psychological mechanisms such as expectation, attention and distraction, and negative and positive affect.
The periaqueductal gray (PAG) is a key anatomic structure in the pain modulation system.158,159 As shown in Figure 1, the PAG is an anatomic relay from limbic forebrain and midbrain structures to the brainstem. The amygdala, hypothalamus, and frontal neocortex all send fibers to the PAG, which connects with relay systems in the pons and medulla.159 These relay systems contain serotonergic neurons such as those in the rostral-ventromedial medulla (RVM) as well as noradrenergic neurons such as those in the dorsolateral pontine tegmentum (DLPT).160 The RVM sends projections to the dorsal horn directly, whereas the DLPT affects dorsal horn neurons indirectly by its projections to the RVM as well as having direct connections (inhibitory only) to the dorsal horn. The RVM has 2 types of cells important in pain perception: "on cells," which facilitate pain transmission; and "off cells," which inhibit pain perception.158
The on and off cells in the RVM through data transmitted from the limbic forebrain and other structures transmitted through the PAG may amplify or dampen pain impulses transmitted from the periphery. Activation of the RVM off neurons or the DLPT neurons via electrical stimulation depresses the activity of nociceptive neurons in the spinal dorsal horn.158,160 These bidirectional on/off systems determine vigilance to either external threats or sensations coming from inside the body.158,161 Limbic structures, the PAG, and these on and off cells determine affect and attention to peripheral stimuli. Normally, this system has a modulatory effect, tending to dampen signals coming in from the body so that these signals are suppressed, allowing attention to be focused on more important events outside of the body.159,161 However, with depletion of serotonin and norepinephrine, as occurs in depression, this system may lose its modulatory effect such that minor signals from the body are amplified, and more attention and emotion are focused on them. This explanation may tell us why patients with depression describe multiple pain symptoms and why their pain is often associated with increased attention, focus, and negative affect.
Studies have shown that the PAG and relay sites in the midbrain, medulla, amygdala, and dorsal horn are rich in endogenous opioids such as enkephalins.158,162 Experimental studies have shown that morphine applied at any of the above sites of the descending pain modulatory system (limbic cortex, midbrain, medulla, or dorsal horn) blocks peripheral pain signals.158,162 Serotonin and norepinephrine given intrathecally also block pain signals.158,160 By increasing levels of serotonin and norepinephrine availability in key brain areas, antidepressants also have effects on modulating pain signals.163 This effect of antidepressants may be greatest for medications that increase availability of serotonin and norepinephrine.163
Studies have shown that brain regions involved in the generation of emotion (eg, the medial prefrontal, insular, and anterior temporal cortex, hypothalamus, and amygdala) send many projections to brainstem structures involved in pain modulation (PAG and RVM).158 Studies have shown that the activity of the anterior cingulate gyrus increases with peripheral pain stimuli, such as heat applied to the skin, but it also has increased activity when warm stimuli are applied if the patient is expecting hot stimuli.158,164,165 Negative anticipation causes key brain areas to activate, and the subject then appears to focus, attend to, and rate the pain stimuli as more severe. Distraction from pain signals in experimental pain has been shown in other experiments to decrease activation of PAG and decrease pain perception.164,165 Also, opiates excite off cells and inhibit on cells. These 2 effects help suppress pain signals. Perhaps these experiments suggest how depression, which is associated with negative expectancies, may amplify pain signals by activating brain structures such as the anterior cingulate gyrus. Depression is also associated with depletion of serotonin and norepinephrine, which may decrease the modulatory effect of this descending pain system.
Several key themes emerged from our review of the relationship between depression and pain. First of all, the prevalence of pain in a depressed sample and the prevalence of depression in a pain sample are higher than the prevalence rates when the conditions are individually examined. On average, 65% of patients with depression experience one or more pain complaints, and depression is present in 5% to 85% (depending on the study setting) of patients with pain conditions. Depression is most prevalent in pain, psychiatric, and specialty clinics vs population-based or primary care studies.
Second, the presence of pain negatively affects the recognition and treatment of depression. Depression is often underrecognized and thus frequently undertreated. At least 75% of primary care patients with depression present with physical complaints exclusively92,166 and seldom attribute their pain symptoms to depression or other psychiatric illness. These physical complaints may be due to amplification of chronic physical disease and remain medically unexplained after extensive workup. As a result, providers frequently assess for physical causes of pain and treat medically instead of exploring the pain symptoms in a broader, biopsychosocial context.
Primary care providers should recognize that pain is a common symptom of depression, that depression and painful conditions frequently coexist, and that evaluation and treatment of both are important. At least in primary care settings, the typical depression presentation is complicated more often by painful symptoms and physical complaints than emotional symptoms of sad mood or anhedonia. The patient who presents "looking depressed" is not difficult to recognize for most providers but may represent the minority of patients with depression seen in primary care.
Recognition would likely be improved by screening for depression in any patient with unexplained pain or unexplained exacerbation of a stable painful condition. Often patients are referred to specialists with expertise in treating pain or expertise in treating depression rather than to a provider who is comfortable treating both. Primary care physicians seem to be in the best position to manage both conditions but may lack the knowledge and experience to tackle this difficult but common clinical situation. Also, the short visit times, inadequate reimbursement, and competing demands on the primary care physician can interfere with optimal management of these complex conditions.167,168
Different aspects of pain negatively affect several depression outcomes. Increasing pain severity, pain that interferes with daily activities, frequent pain episodes, diffuse pain, and pain that is refractory to treatment are all associated with more depressive symptoms and more severe depression. Additionally, as pain severity worsens, other depression outcomes such as functional limitations, health-related quality of life, and work function are adversely affected. Pain with comorbid depression also appears to be additive in terms of an increased number of medical visits and higher health care costs. The prognosis of comorbid depression and pain is poor compared with the prognosis for individuals with depression without pain.169 What is not clear is whether patients with depression and pain are less responsive to usual depression management than those with depression alone.
Our literature review establishes the reciprocal nature of the depression-pain relationship. Depression complicates the management of patients with pain and is associated with poorer outcomes. In patients with pain, depression is associated with more pain complaints, greater pain intensity, longer duration of pain, and greater likelihood of nonrecovery. Additive impairments in social function, work function, and functional limitations (eg, limited mobility and restricted activity) are seen when depression and pain coexist. Depression also predicts increased health care utilization, poorer adherence to treatment, worse patient satisfaction, and future episodes of pain.
Most studies that examined antidepressant treatment of pain conditions suggested that pain and depression symptoms improved simultaneously, with the caveats that most of these studies were uncontrolled, of short duration, and designed more to measure pain response. Tricyclic antidepressants have been the predominant therapy evaluated. Preliminary data suggest that some of the newer antidepressants, including agents that act on several receptors (eg, norepinephrine and serotonin), may be useful in chronic pain.170-173 However, larger clinical trials on non–tricyclic antidepressants in patients with comorbid depression and pain are needed. Unfortunately, very few depression treatment trials have assessed whether pain improves in concert with depression symptoms and whether greater improvement in pain or depression relates to greater improvement in the other condition. Despite the promising findings that depression and pain respond to antidepressant therapy, many patients are treated primarily with pain-relieving medications that have little intrinsic antidepressant effect.
Recent research has provided evidence of a central pain modulation system that can either dampen or amplify nociceptive signals from the periphery. Both serotonin and norepinephrine have been shown to dampen peripheral pain signals. This explains how depression, which is associated with a dysregulation of these key modulating neurotransmitters along a shared pathway, may contribute to the frequent presence of painful symptoms. Thus the decrease in one or both of these neurotransmitters may increase peripheral pain messages and affect how antidepressants that increase these neurotransmitters decrease pain signals.
In summary, the combination of depression and pain is associated with worse clinical outcomes than either condition alone. Thus, a treatment model that incorporates assessment and treatment of both depression and pain seems necessary for more optimal outcomes. More research is needed to determine if alleviation of pain helps the patients' depressive symptoms and, likewise, whether relief of depressive symptoms improves pain and its related morbidity. Inattention to pain can cause refractoriness to depression treatment and not addressing depression can preclude successful pain treatment.Dual therapy trials are needed to see if depression and pain outcomes can be improved with attention to their comorbidity.
Corresponding author and reprints: Matthew J. Bair, MD, MS, Richard L. Roudebush VA Medical Center, Mail Code 11-H, 1481 W 10th St, Indianapolis, IN 46202 (e-mail: email@example.com).
Accepted for publication January 31, 2003.
This project was supported in part by grant T-32 PE15001 from the Health Resources and Service Administration and by funding from Eli Lilly and Company, Indianapolis, Ind.
Dr Bair has received grant support from Eli Lilly and Company. Ms Robinson is currently employed by Eli Lilly and Company. Dr Katon has received honoraria from Eli Lilly and Company, GlaxoSmithKline, Wyeth-Ayerst Laboratories, Pfizer Inc, and Forest Pharmaceuticals Inc and sits on the advisory boards for Eli Lilly and Company, GlaxoSmithKline, and Wyeth-Ayerst Laboratories. Dr Kroenke has received honoraria, compensation as a consultant, or grant support form Eli Lilly and Company, Pfizer Inc, GlaxoSmithKline, and Bristol-Myers Squibb Company.
et al. The NIMH Epidemiologic Catchment Area program: historical context, major objectives, and study population characteristics. Arch Gen Psychiatry.
1984;41934- 941PubMedGoogle ScholarCrossref
AL "Minor" illness symptoms: the magnitude of their burden and of our ignorance. Arch Intern Med.
1990;1501586- 1587PubMedGoogle ScholarCrossref
AD Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet.
1997;3491498- 1504PubMedGoogle ScholarCrossref
S Managing pain and comorbid depression: a public health challenge. Semin Clin Neuropsychiatry.
1999;4203- 220PubMedGoogle Scholar
FV Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci.
2001;2637- 43PubMedGoogle Scholar
E Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits. Ann Intern Med.
2001;134917- 925PubMedGoogle ScholarCrossref
MD Depression and chronic medical illness. J Clin Psychiatry.
3- 11PubMedGoogle Scholar
DP Somatic presentation of DSM III
psychiatric disorders in primary care. J Psychosom Res.
1985;29563- 569PubMedGoogle ScholarCrossref
MJ Somatization and the recognition of depression and anxiety in primary care. Am J Psychiatry.
1993;150734- 741PubMedGoogle Scholar
CB Depression in patients with cancer: diagnosis, biology, and treatment. Arch Gen Psychiatry.
1995;5289- 99PubMedGoogle ScholarCrossref
JL Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med.
2000;15659- 666PubMedGoogle ScholarCrossref
K Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med.
2000;10865- 72PubMedGoogle ScholarCrossref
JE Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med.
2001;11154- 63PubMedGoogle ScholarCrossref
K Impact of pain on depression treatment response in primary care. Psychosom Med.
In press.Google Scholar
N Anxiety and depression in an outpatient clinic in Lesotho, Africa. Int J Psychiatry Med.
1994;24179- 188PubMedGoogle ScholarCrossref
GF A note on the occurrence of pain in psychiatric patients from a Canadian Indian and Inuit population. Pain.
1981;1075- 78PubMedGoogle ScholarCrossref
H The prevalence of current major depression and dysthymia in a Norwegian general practice. Acta Psychiatr Scand.
1997;95324- 328PubMedGoogle ScholarCrossref
et al. Pain as a symptom in depressive disorders, I: relationship to diagnostic subgroup and depressive symptomatology. Pain.
1983;1519- 26Google ScholarCrossref
RO The effectiveness of tricyclic antidepressants in the treatment of coexisting pain and depression. Pain.
1979;7331- 341PubMedGoogle ScholarCrossref
G Depressive and distress symptoms as predictors of low back pain, neck-shoulder pain, and other musculoskeletal morbidity: a 10-year follow-up of metal industry employees. Pain.
1993;5389- 94PubMedGoogle ScholarCrossref
AJ Psychologic distress and low back pain: evidence from a prospective study in the general population. Spine.
1995;202731- 2737PubMedGoogle ScholarCrossref
et al. Physical symptoms in primary care: predictors of psychiatric disorders and functional impairment. Arch Fam Med.
1994;3774- 779PubMedGoogle ScholarCrossref
RS Chronic pain-associated depression: antecedent or consequence of chronic pain? a review. Clin J Pain.
1997;13116- 137PubMedGoogle ScholarCrossref
MA Is chronic pain a variant of depressive illness? a critical review. Can J Psychiatry.
1986;31241- 248PubMedGoogle Scholar
R The treatment of depression in chronic low back pain: review and recommendations. Pain.
1992;505- 13PubMedGoogle ScholarCrossref
T The relationship of chronic pain, mental illness and organic disorders. Pain.
1988;32185- 195PubMedGoogle ScholarCrossref
M Second-year follow-up study on systematic treatment of chronic pain with antidepressants. Henry Ford Hosp Med J.
1981;2967- 68PubMedGoogle Scholar
H Male and female chronic pain patients categorized by DSM-III
psychiatric diagnostic criteria. Pain.
1986;26181- 197PubMedGoogle ScholarCrossref
IM Depression as a psychopathological disorder in chronic low back pain patients. J Psychosom Res.
1986;30127- 133PubMedGoogle ScholarCrossref
JM Depression in chronic pain patients: relation to pain, activity, and sex differences. Pain.
1985;23337- 343PubMedGoogle ScholarCrossref
M Stress-related, posttraumatic chronic pain syndrome: criteria for diagnosis, and preliminary report on prevalence. Pain.
1985;23295- 300PubMedGoogle ScholarCrossref
SI Psychiatric diagnosis of chronic pain patients. Am J Psychiatry.
1983;1401495- 1498PubMedGoogle Scholar
DP MMPI subgroups and affective disorder in chronic pain patients. J Nerv Ment Dis.
1986;174408- 413PubMedGoogle ScholarCrossref
L Denial in the depressive and pain-prone disorders of chronic pain. Fields
Feds. Proceedings of the Fourth World Congress on Pain (Advances in Pain Research and Therapy).
New York, NY Raven Press1985;879- 888Google Scholar
D Chronic pain: lifetime psychiatric diagnoses and family history. Am J Psychiatry.
1985;1421156- 1160PubMedGoogle Scholar
T Are patients with chronic pain depressed? Am J Psychiatry.
1983;140747- 749PubMedGoogle Scholar
BJ Chronic pain and depression, II: symptoms of anxiety in chronic low back pain patients and their relationship to subtypes of depression. Pain.
1985;22289- 294PubMedGoogle ScholarCrossref
A A prospective DSM-III
study of 100 consecutive somatization patients. Compr Psychiatry.
1984;25305- 314PubMedGoogle ScholarCrossref
H A simple examination of the relationships between pain, organic lesions and psychiatric illness. Pain.
1987;29295- 300PubMedGoogle ScholarCrossref
et al. Screening for psychiatric morbidity: the pattern of psychological illness and premorbid characteristics in four chronic pain populations. Pain.
1987;30141- 157PubMedGoogle ScholarCrossref
WM Psychologic characteristics of psychiatric patients having pain as a presenting symptom. CMAJ.
1967;97387- 394PubMedGoogle Scholar
JE Psychiatric disorders associated with atypical facial pain. Can J Psychiatry.
1983;28178- 181PubMedGoogle Scholar
RM Chronic pain and depression: a clinical and family history survey. Am J Psychiatry.
1980;137118- 120PubMedGoogle Scholar
SR Depressed mood in chronic low back pain: relationship with stressful life events. Pain.
1988;3547- 55PubMedGoogle ScholarCrossref
G Pain syndromes involving the locomotor apparatus: a possible manifestation of masked depression. Kielhoz
Ped. Depression in Everyday Practice
Vienna, Austria Hans Huber Publishers1974;Google Scholar
S Atypical facial pain and psychogenic origin: a masked depression syndrome. Lesse
Sed. Masked Depression
New York, NY Jason Aronson Inc1974;Google Scholar
et al. Psychiatric diagnoses and sexual victimization in women with chronic pelvic pain. Psychosomatics.
1995;36531- 540PubMedGoogle ScholarCrossref
AW Depression in chronic low back pain patients: diagnostic efficiency of three self-report questionnaires. J Clin Psychol.
1987;4384- 89PubMedGoogle Scholar
P The Saskatchewan Health and Back Pain Survey: the prevalence and factors associated with depressive symptomatology in Saskatchewan adults. Can J Public Health.
2000;91459- 464PubMedGoogle Scholar
G Psychosocial correlates and impact of chronic tension-type headaches. Headache.
2000;403- 16PubMedGoogle ScholarCrossref
et al. Factors that modify the association between knee pain and mobility limitation in older women: the Women's Health and Aging Study. Ann Rheum Dis.
2000;59331- 337PubMedGoogle ScholarCrossref
H Chronic musculoskeletal pain and depressive symptoms in the general population: an analysis of the 1st National Health and Nutrition Examination Survey data. Pain.
1990;43299- 307PubMedGoogle ScholarCrossref
SR Chronic musculoskeletal pain and depressive symptoms in the National Health and Nutrition Examination, I: epidemiologic follow-up study. Pain.
1993;53163- 168PubMedGoogle ScholarCrossref
MA Affective, substance use, and anxiety disorders in persons with arthritis, diabetes, heart disease, high blood pressure, or chronic lung conditions. Gen Hosp Psychiatry.
1989;11320- 327PubMedGoogle ScholarCrossref
RK Symptoms in the community: prevalence, classification, and psychiatric comorbidity. Arch Intern Med.
1993;1532474- 2480Google ScholarCrossref
H Association between major depressive disorder and physical illness. Psychol Med.
1993;23755- 761PubMedGoogle ScholarCrossref
R Persistent pain and well-being: a World Health Organization Study in Primary Care. JAMA.
1998;280147- 151[erratum appears in JAMA.
SB Long-term medical conditions and major depression in a Canadian population study at waves 1 and 2. J Affect Disord.
2001;6335- 41PubMedGoogle ScholarCrossref
K Somatic symptoms: a major feature of depression in a family practice. J Affect Disord.
1983;5199- 207PubMedGoogle ScholarCrossref
Y Patients' reasons for not presenting emotional problems in general practice consultations. Br J Gen Pract.
1999;49875- 879PubMedGoogle Scholar
JM Three forms of somatization in primary care: prevalence, co-occurrence, and sociodemographic characteristics. J Nerv Ment Dis.
1991;179647- 655PubMedGoogle ScholarCrossref
J An international study of the relation between somatic symptoms and depression. N Engl J Med.
1999;3411329- 1335PubMedGoogle ScholarCrossref
P Antidepressants in the medically ill: diagnosis and treatment in primary care. Clin Chem.
1988;34829- 836PubMedGoogle Scholar
HJ Depression among high utilizers of medical care. J Gen Intern Med.
1999;14461- 468PubMedGoogle ScholarCrossref
W Depression: relationship to somatization and chronic medical illness. J Clin Psychiatry.
1984;454- 12PubMedGoogle Scholar
et al. The relationship of presenting physical complaints to depressive symptoms in primary care patients. J Gen Intern Med.
1992;7170- 173PubMedGoogle ScholarCrossref
et al. Psychosocial care by general practitioners—where are the problems? results of a demonstration project on quality management in psychosocial primary care. Int J Psychiatry Med.
1999;29395- 409PubMedGoogle ScholarCrossref
EH Disability and depression among high utilizers of health care: a longitudinal analysis. Arch Gen Psychiatry.
1992;4991- 100PubMedGoogle ScholarCrossref
G The relationship between pain and depression. Br J Psychiatry Suppl.
1996;30101- 108PubMedGoogle Scholar
W Predicting poor outcomes for back pain seen in primary care using patients' own criteria. Spine.
1996;212900- 2907PubMedGoogle ScholarCrossref
B Clinical factors associated with short-term changes in outcome of patients with somatized mental disorder in primary care. Psychol Med.
1998;28703- 711PubMedGoogle ScholarCrossref
et al. Neuroticism and extraversion as predictors of health outcomes in depressed primary care patients. Psychosomatics.
1997;38339- 348PubMedGoogle ScholarCrossref
RJ Depression in primary care: changes in pattern of patient visits and complaints during a developing depression. J Fam Pract.
1978;7293- 302PubMedGoogle Scholar
RJ Depression in family practice: changes in pattern of patient visits and complaints during subsequent developing depressions. J Fam Pract.
1979;91017- 1021PubMedGoogle Scholar
TW A national study of the effect of chronic pain on the use of health care by depressed persons. Psychiatr Serv.
2003;54683- 697Google ScholarCrossref
GP Comparison of two dosage regimens of fluoxetine in major depression. J Clin Psychiatry.
1985;4638- 41PubMedGoogle Scholar
et al. National Institute of Mental Health Treatment of Depression Collaborative Research Program: general effectiveness of treatments. Arch Gen Psychiatry.
1989;46971- 982Google ScholarCrossref
EC Evolution of remission as the new standard in the treatment of depression. J Clin Psychiatry.
7- 11PubMedGoogle ScholarCrossref
A Residual symptoms after partial remission: an important outcome in depression. Psychol Med.
1995;251171- 1180PubMedGoogle ScholarCrossref
et al. Biofeedback and relaxation training with three kinds of headache: treatment effects and their prediction. J Consult Clin Psychol.
1982;50562- 575PubMedGoogle ScholarCrossref
S Psychosocial predictors of outcome in acute and subchronic low back trouble. Spine.
1995;20722- 728PubMedGoogle ScholarCrossref
H Predicting long-term functional limitations among back pain patients in primary care settings. J Clin Epidemiol.
1997;5031- 43PubMedGoogle ScholarCrossref
JA Depression among chronic pain patients: cognitive-behavioral analysis and effect on rehabilitation outcome. J Consult Clin Psychol.
1988;56870- 876PubMedGoogle ScholarCrossref
JM The evolution of chronic pain among patients with musculoskeletal problems: a pilot study in primary care. Br J Gen Pract.
1992;42462- 464PubMedGoogle Scholar
L Predictors of low back pain onset in a prospective British study. Am J Public Health.
2001;911671- 1678PubMedGoogle ScholarCrossref
A A new look at low back complaints in primary care: a RAMBAM Israeli Family Practice Research Network study. J Fam Pract.
1999;48299- 303PubMedGoogle Scholar
ME Influence of psychological factors on postoperative pain, mood and analgesic requirements. Pain.
1986;24331- 342PubMedGoogle ScholarCrossref
SF First onset of common pain symptoms: a prospective study of depression as a risk factor. Pain.
1993;55251- 258PubMedGoogle ScholarCrossref
L Predicting treatment response in depressed and non-depressed chronic pain patients. Pain.
1986;24343- 353PubMedGoogle ScholarCrossref
ACN Intrinsic patient variables and outcome in the behavioral treatment of recurrent pediatric headache. DC
EJeds. Pediatric Pain (Advances in Pain Research and Therapy)
New York, NY Raven Press;1990;Google Scholar
R Controlled trial of imipramine for chronic low back pain. J Fam Pract.
1982;14841- 846PubMedGoogle Scholar
G Systematic treatment of chronic pain with antidepressants. Henry Ford Hosp Med J.
1980;2815- 21PubMedGoogle Scholar
et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med.
1994;3301411- 1417PubMedGoogle ScholarCrossref
F The relationship between pain and depression in a trial using paroxetine in sufferers of chronic low back pain. Psychosomatics.
2000;41490- 499PubMedGoogle ScholarCrossref
M A clinical trial of Tofranil in rheumatic pain in general practice. J Int Med Res.
1976;441- 49PubMedGoogle Scholar
MO A controlled study of a serotonin reuptake blocker, zimelidine, in the treatment of chronic pain. Pain.
1986;2535- 52PubMedGoogle ScholarCrossref
et al. Doxepin effects on chronic pain, depression and plasma opioids. J Clin Psychiatry.
1982;4322- 27PubMedGoogle Scholar
et al. Doxepin's effects on chronic pain and depression: a controlled study. J Clin Psychiatry.
1984;4547- 53PubMedGoogle Scholar
CD Tofranil in the treatment of low back pain. J Int Med Res.
1976;428- 40PubMedGoogle Scholar
L A double-blind controlled study of serotonin uptake inhibitor (Zimelidine) versus placebo in chronic pain patients. Pain.
1979;769- 78PubMedGoogle ScholarCrossref
P Clomipramine and mianserin in chronic idiopathic pain syndrome: a placebo controlled study. Psychopharmacology.
1989;991- 7PubMedGoogle ScholarCrossref
L Chronic tension-type headache, mood depression and serotonin: therapeutic effects of fluvoxamine and mianserine. Headache.
1994;3444- 49PubMedGoogle ScholarCrossref
RK A controlled study of amitriptyline in the treatment of chronic pain. Pain.
1982;14169- 179PubMedGoogle ScholarCrossref
HC Drug treatment of chronic intractable pain in patients referred to a psychiatry clinic. J Indian Med Assoc.
1971;56341- 345PubMedGoogle Scholar
MA Treatment of the painful shoulder syndrome with amitriptyline and lithium carbonate. CMAJ.
1974;111137- 140PubMedGoogle Scholar
D Antidepressants in concomitant chronic back pain and depression: doxepin and desipramine compared. J Clin Psychiatry.
1984;4554- 57PubMedGoogle Scholar
K Antidepressant therapy for unexplained symptoms and symptom syndromes. J Fam Pract.
1999;48980- 990PubMedGoogle Scholar
GD Acute effects of fluoxetine versus placebo on functional health and well-being in late-life depression. Int Psychogeriatr.
125- 137PubMedGoogle ScholarCrossref
et al. Impact of improved depression treatment in primary care on daily functioning and disability. Psychol Med.
1998;28693- 701PubMedGoogle ScholarCrossref
R Cognitive-behavioral therapy for somatization and symptom syndromes: a critical review of controlled clinical trials. Psychother Psychosom.
2000;69205- 215PubMedGoogle ScholarCrossref
M The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med.
1997;12384- 389PubMedGoogle ScholarCrossref
H Pain modulation: expectations, opioid analgesia and virtual pain. Prog Brain Res.
2000;122245- 253PubMedGoogle Scholar
K Effects of electrical stimulation of thalamic nucleus submedius and periaqueductal gray on the visceral nociceptive responses of spinal dorsal horn neurons in the rat. Brain Res.
1999;834112- 121PubMedGoogle ScholarCrossref
HL Highly delta selective antagonists in the RVM attenuate the antinociceptive effect of PAG DAMGO. Neuroreport.
1999;103125- 3129PubMedGoogle ScholarCrossref
HL Cholecystokinin and enkephalin in brain stem pain modulating circuits. Neuroreport.
1997;82995- 2998PubMedGoogle ScholarCrossref
ME Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci.
2001;2630- 36PubMedGoogle Scholar
MC Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science.
1997;277968- 971PubMedGoogle ScholarCrossref
et al. Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci.
2000;207438- 7445PubMedGoogle Scholar
J Depressive and anxiety disorders in patients presenting with physical complaints: clinical predictors and outcome. Am J Med.
1997;103339- 347PubMedGoogle ScholarCrossref
MS Competing demands in psychosocial care: a model for the identification and treatment of depressive disorders in primary care. Gen Hosp Psychiatry.
1997;1998- 111PubMedGoogle ScholarCrossref
W Longitudinal relationship between pain and depression in older adults: sex, age and physical disability. Soc Psychiatry Psychiatr Epidemiol.
2002;3723- 30PubMedGoogle ScholarCrossref
H Venlafaxine for the treatment of chronic pain. Am J Psychiatry.
1996;153- 737PubMedGoogle Scholar
KA Breast pain associated with venlafaxine. J Clin Psychiatry.
1996;57- 423PubMedGoogle Scholar
RM Evaluating and treating comorbid pain and depression. Int Rev Psychiatry.
2000;12103- 114Google ScholarCrossref
MA Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry.
2002;63308- 315PubMedGoogle ScholarCrossref