depression and pain comorbidity

Depression and Pain Comorbidity

A Literature Review

Matthew J. Bair, MD, MS; Rebecca L. Robinson, MS; Wayne Katon, MD; Kurt Kroenke, MD

B ecause depression and painful symptoms commonly occur together, we conducted aliterature review to determine the prevalence of both conditions and the effects of co-morbidity on diagnosis, clinical outcomes, and treatment. The prevalences of pain indepressed cohorts and depression in pain cohorts are higher than when these condi-

tions are individually examined. The presence of pain negatively affects the recognition and treat-ment of depression. When pain is moderate to severe, impairs function, and/or is refractory to treat-ment, it is associated with more depressive symptoms and worse depression outcomes (eg, lowerquality of life, decreased work function, and increased health care utilization). Similarly, depres-sion in patients with pain is associated with more pain complaints and greater impairment. De-pression and pain share biological pathways and neurotransmitters, which has implications forthe treatment of both concurrently. A model that incorporates assessment and treatment of de-pression and pain simultaneously is necessary for improved outcomes.

Arch Intern Med. 2003;163:2433-2445

Individually, depression and pain symp-toms are highly prevalent conditions en-countered by primary care physicians andspecialists. Epidemiologic studies indi-cate that the lifetime prevalence of painsymptoms (eg, joint pain, back pain, head-ache, chest pain, arm or leg pain, and ab-dominal pain) ranges from 24% to 37%1

and that physical symptoms such as painare the leading reason that patients seekmedical care.2,3 Major depression is alsocommon, with prevalence in primary carepatients of 5% to 10%.4 This underesti-mates the true impact of depression, sincemany more people have depressive symp-toms but do not fully meet the major de-pressive disorder diagnostic criteria of theAmerican Psychiatric Association’s Diag-nostic and Statistical Manual of Mental Dis-

orders, Fourth Edition for duration or num-ber of symptoms. Depression has becomethe fourth leading cause of disability world-wide and is projected to become even moreburdensome in the future.5

A growing body of literature has fo-cused on the interaction between depres-sion and pain symptoms. This interac-tion has been labeled by some authors asthe depression-pain syndrome6 or depres-sion-pain dyad, implying that the condi-

tions often coexist, respond to similar treat-ments, exacerbate one another, and sharebiological pathways and neurotransmit-ters.7,8 Patients with depression often pre-sent with a complex set of overlappingsymptoms, including emotional and physi-cal complaints. Physical complaints typi-cally include medically unexplained pain.9

Although it is generally understood thatdepression and painful symptoms are com-mon comorbidities and that their combi-nation is costlier and more disabling than

For editorial comment seepage 2415

Author affiliations appear at the end of this article. Dr Bair has received grant supportfrom Eli Lilly and Company. Ms Robinson is currently employed by Eli Lilly andCompany. Dr Katon has received honoraria from Eli Lilly and Company,GlaxoSmithKline, Wyeth-Ayerst Laboratories, Pfizer Inc, and Forest PharmaceuticalsInc and sits on the advisory boards for Eli Lilly and Company, GlaxoSmithKline, andWyeth-Ayerst Laboratories. Dr Kroenke has received honoraria, compensation as aconsultant, or grant support form Eli Lilly and Company, Pfizer Inc, GlaxoSmithKline,and Bristol-Myers Squibb Company.

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either condition alone, their inter-action is not fully understood. Un-derstanding this relationship has be-come more important, given thatprimary care physicians fail to ac-curately diagnose at least 50% of pa-tients with major depression,10 andat least 2 studies have shown that pa-tients with depression who presentwith physical symptoms such as painare particularly likely to receive aninaccurate diagnosis.11,12 Patientswith depression have significantlymore unexplained physical symp-toms such as pain and fatigue andutilize more health resources thannondepressed patients. The new em-phasis on pain as the fifth vital signby the Joint Commission onAccreditation of Healthcare Orga-nizations and the Veterans HealthAdministration highlights the im-portance of a better understandingof the likely reciprocal links be-tween depression and pain.

The present review addressesthe following 6 questions: (1) Whatis the prevalence of pain symptomsin patients with depression and, con-versely, what is the prevalence of de-pression in patients with pain com-plaints? (2) Does the presence ofpain affect provider recognition andtreatment of depression? (3) Doesthe presence of pain affect depres-sion outcomes such as functionallimitations, quality of life, health carecosts and utilization, and treat-ment efficacy? (4) Does the pres-ence of depression affect these sameclinical outcomes in patients treatedfor pain? (5) Is antidepressant treat-

ment for painful symptoms and co-morbid depression effective? and (6)What are the common biologicalpathways and implications for treat-ment choice when depression andpain coexist?

METHODS

We searched the MEDLINE databasefrom 1966 through July 30, 2002, us-ing the combined search terms depres-sion or depressive disorders and pain. Ar-ticles were also identified by a manualsearch of bibliographies from all re-trieved articles. Studies were limited tohuman studies reported in English. A fewabstracts, studies not published in full,and book chapters were included. Twoof us (M.J.B. and K.K.) independentlyscreened titles and abstracts and reachedagreement on which articles to re-trieve. All primary and review articleswere examined for information perti-nent to our questions.

Studies were eligible for inclusion ifthey addressed both depression and painsymptoms. Specific symptoms (eg, head-ache, back pain, neck pain, extremity/joint pain, chest pain, pelvic pain, ab-dominal pain, and others) as well asgeneral pain (ie, studies that used painmeasures but did not specify pain loca-tion) were included in the analysis. Ar-ticles were included if they had primarydata derived from clinical trials or lon-gitudinal or cross-sectional studies. Ex-cluded studies were those addressing paindue to specific disease processes (eg, pe-ripheral neuropathy, rheumatoid arthri-tis, or cancer pain) or symptom syn-dromes (eg, fibromyalgia, irritable bowelsyndrome, or migraine headache) be-cause these conditions have been the sub-ject of previous reviews.13-20

Because of the broad scope of de-pression and painful symptoms, the va-riety of measures used to assess depres-sion, and the different study definitionsof pain, formal meta-analytic methodswere precluded. Instead, this review isa qualitative and semiquantitative syn-thesis of the relevant, representative, andevidence-based literature.

RESULTS

WHAT IS THE PREVALENCEOF PAIN SYMPTOMS IN

PATIENTS WITH DEPRESSION?

To address the prevalence of depres-sionandpainsymptoms,wesumma-rized the literature based on whetherthe subjects presented with depres-sion and were then assessed for pain(14articles)or ifpatientswithapain-ful condition were assessed for de-pression (42 articles). Fourteenstudies6,21-33 were identified that fo-cusedontheprevalenceofpainsymp-toms in patients with depression(Table 1). The prevalence of painranged from 15% to 100% (meanprevalence, 65%). Most of the stud-ieswereuncontrolledandperformedin psychiatric settings. Only 3 stud-ies6,24,29 examined primary care pa-tients, and 2 studies solicited com-munityvolunteers.25,32Theprevalencerates do not appear to be influencedby thestudysetting in that theredoesnot seem to be a different prevalenceinpsychiatricvsprimarycaresettings.Sample sizes were modest, rangingfrom 16 to 573 patients (mean, 137).Pain was primarily assessed at the

Table 1. Pain Symptoms in Patients With Depression

Source No. of Patients Study Setting Pain Type Patients With Pain, %

Bair et al21 573 Primary care Mulitple pain sites 69Delaplaine et al22 29 Psychiatric inpatients Multiple pain sites 51Diamond23 432 Neurology clinic Headache 85Hollifield et al24 29 Outpatient clinic “Pain” complaints 59Lindsay and Wyckoff6 196 Private practice Chronic pain �3 mo 59Mathew et al25 51 Research institution Physical symptoms 77 (Headache),

37 (chest pain)Merskey and Spear26 85 Psychiatric patients Pain sites 56Pelz et al27 22 Psychiatric patients Multiple pain sites 41Singh28 150 Depressed outpatients “Physical complaints” 65Vaeroy and Merskey29 28 General practice Pain problem 43von Knorring30 40 Psychiatric inpatients “All types” 60von Knorring et al31 161 Psychiatric inpatients “Aches and pain” 57Ward et al32 16 Respondents to newspaper advertisement Multiple pain sites 100Watts33 100 Psychiatric patients Variety 15




clinical interview or self-assessed bythe patient presenting with the paincomplaint.Thedefinitionofpaincon-dition, location of pain, and durationofpaincomplaintvariedconsiderablyamongstudies.Severaldifferentscaleswere used to assess depression.

A large longitudinal cohortstudy has shown that depressivesymptoms predict future episodes oflow back pain, neck-shoulder pain,and musculoskeletal symptomscompared with those patients with-out depressive symptoms at base-line.34 Another study showed thatlow back pain is more than 2 timesas likely to be reported by individu-als with depressive symptoms com-pared with those without depres-sive symptoms.35 In addition, thespecific complaints of headache, ab-dominal pain, joint pain, and chestpain are frequently reported by pa-tients with depression in primarycare settings25,36 and by elderly nurs-ing home residents.37

WHAT IS THE PREVALENCEOF MAJOR DEPRESSION IN

PAIN PATIENTS?

Several reviews38-42 have examinedthe prevalence of major depressionin patients with pain. Table 2summarizes 42 studies6,36,43-82 iden-tified by our literature search. Fif-teen studies were from pain clinicsor inpatient pain programs; 9 frompsychiatric clinics or psychiatricconsultation; 3 from arthritis,rheumatology, or orthopedic clin-ics (excluding rheumatoid arthritisand fibromyalgia studies); 3 fromdental/facial pain clinics; 2 fromsurgical patients; and 10 from pri-mary care or population-based set-tings. Most studies (n=31) focusedon “chronic” pain complaints of atleast 6 months’ duration.

The mean (range) prevalencerates for concurrent major depres-sion in patients identified as hav-ing pain by study setting are as fol-lows: 52% (1.5%-100%) in painclinics or inpatient pain programs;38% (6%-64%) in psychiatric clin-ics or psychiatric consultation; 56%(21%-89%) in orthopedic clinics orrheumatology clinics (excludingstudies focusing on fibromyalgia orrheumatoid arthritis); 85% (35%-100%) in dental clinics addressing

facial pain; 13% (12%-17%) in gy-necology clinics addressing chronicpelvic pain in laparoscopy patients;18% (4.7%-22%) in population-based settings; and 27% (5.9%-46%) in primary care clinics. In ad-dition to the point prevalence rateslisted in Table 2, two studies54,73 alsoreported the lifetime prevalence ofmajor depression in pain patients.Rates of depression increased from12% to 32%73 and 32.4% to 56.8%,54

respectively. When the etiology ofthe pain condition is considered,studies of more defined pain disor-ders (eg, peripheral neuropathy) re-port lower occurrence of depres-sion than studies of medicallyunexplained pain.61

A variety of instruments wereused to diagnose depression, includ-ing the Beck Depression Inventory,Center for Epidemiological StudiesDepression Scale, Primary CareEvaluation for Mental Disorders,Geriatric Depression Scale, Feigh-ner criteria, and Hopkins SymptomChecklist. Pain was assessed mainlythrough clinical interview or differ-ent pain questionnaires. The sub-stantial variation in prevalence ratesis likely related to differences in di-agnostic criteria used for depres-sion, pain conditions examined, studydesigns, and subject populations.

Severalstudieshavereportedtheassociation between depression andpain, specifically addressing how theriskofdepression increasesasa func-tion of different aspects of worsen-ing pain (eg, severity, frequency, du-ration, and number of symptoms).Patientswithmultiplepainsymptoms(eg, back pain, headache, abdominalpain, chest pain, and facial pain) are3 to 5 times more likely to be de-pressed than patients without pain,81

and pain symptoms are associatedwith at least a 2-fold increased riskforcoexistingdepression.83 Addition-ally,apopulation-basedstudyshowedthat subjects with chronic pain (de-fined as pain for most days for at leasta month) are 3 times as likely to meetdepression criteria as those withoutchronic pain.80 The association be-tween depression and pain becomesstronger as the severity of either con-dition increases. For example, as theseverity of pain increases, depressivesymptoms and depression diagnosesbecome more prevalent.75,77,84 Like-

wise, as depression symptoms in-crease inseverity,paincomplaintsarereported more often.81

Consistent with findings in pri-mary care patients,36 multiple paincomplaints increase the probabilityof depression38 such that patientswith 2 or more different pain com-plaints are 6 times more likely to bedepressed, and patients with 3 ormore pain complaints are 8 timesmore likely to meet depression cri-teria.10 In addition, more frequentpain episodes85 and longer pain du-ration are associated with depres-sion. An international study showedthat patients with pain lasting longerthan 6 months were more than 4times as likely to have a depressivedisorder as those without chronicpain.86 The long-term medical con-ditions most strongly associated lon-gitudinally with the development ofincident depression included backpain and migraine headaches.87

DOES THE PRESENCE OF PAINAFFECT PROVIDERRECOGNITION AND

TREATMENT OF DEPRESSION?

Fourteen studies sought to deter-mine whether the presence of painaffected provider recognition of de-pression. In depression studies notaddressing pain, at least half of pa-tients with major depression werenot properly diagnosed and there-fore not treated for depression in pri-mary care settings.11,88 Althoughmany factors account for this prob-lem, the most important reason re-lates to how the patient presents. The“typical” depression presentation inprimary care is dominated by physi-cal (somatic) complaints as op-posed to psychological complaints.More than 50% of patients with de-pression report somatic complaintsonly11,12,24,89-92 and at least 60% ofthese somatic complaints are pain re-lated.24,25,36,93 Thus, patients with de-pression in primary care settings aremore likely to report various painsymptoms than they are to presentwith dysphoric mood or anhedo-nia. Physical (or somatic) symp-toms of depression, specifically fa-t igue , insomnia , and pa incomplaints, are more numerous inpatients with depression, are fre-quently nonspecific,91,94 and are of-




ten unrelated to a known organicdisease process.3

The patient’s presentation ofphysical complaints (and the promi-nence of pain symptoms) inter-feres with the recognition of depres-sion for patients in primary caresettings. Presentation of progres-sively more physical complaints re-duces depression recognition11,12 be-cause patients and their medical

providers (at least initially) often as-sociate these symptoms with an un-derlying medical illness instead of anunderlying depressive disorder. Pre-vious work has shown that if all pri-mary care patients presenting witha variety of pain conditions (eg, ab-dominal pain, headache, joint pain,and back pain) were evaluated forpossible depression, 60% of previ-ously undetected depression cases

could have been recognized.95 Pa-tients having multiple presentingphysical complaints, including non-specific musculoskeletal com-plaints and back pain, had more un-derlying depressive symptoms.96

Additionally, patients presentingwith somatic complaints are morelikely to have subclinical and mildercases of depression that negativelyaffect recognition: milder cases of de-

Table 2. Major Depression in Patients With Pain

Source No. of Patients Setting Sample Patients With Depression, %

Pain Clinics and Inpatient Pain ProgramsBenjamin et al43 106 Outpatient pain clinic Chronic pain 33Blumer and Heilbronn44 900 Pain clinics Chronic pain 83Covino et al45 44 Pain clinic Chronic pain 100Fishbain et al46 283 Pain clinic Pain �2 y 4.6France et al47 80 Pain clinic Low back pain �6 mo 21Haley et al48 63 Pain clinic Chronic pain 49.2Lindsay and Wyckoff6 300 Pain clinic Chronic pain 87Muse49 64 Pain clinic Pain �6 mo 1.5Turner and Romano50 40 Pain clinic Pain �6 mo 30Reich et al51 43 Pain board Chronic pain 23.2Atkinson et al52 52 Inpatient pain program Chronic low back pain 44Boukoms et al53 62 Inpatient pain program Pain �6 mo 24.2Katon et al54 37 Inpatient pain program Pain �1 y 32.4Kramlinger et al55 100 Inpatient pain program Chronic pain 25-39Krishnan et al56 71 Inpatient pain program Chronic low back pain 45

Psychiatry Clinics and Psychiatry ConsultationChaturvedi57 200 Outpatient psychiatry Chronic pain 61Chaturvedi58 203 Outpatient psychiatry Pain �3 mo 6.9Katon et al59 49 Psychiatric consultation Chronic pain 57.1Large60 50 Psychiatric consultation Pain �6 mo 6.0Magni and Merskey61 137 Psychiatric consultation Pain �6 mo 31.3Merskey et al62 32 Psychiatric consultation Chronic pain 28.1Pilling et al63 182 Psychiatric patients Chronic pain 64Remick et al64 68 Psychiatric consultation Atypical facial pain 13.2Schaffer et al65 20 Psychiatry Back pain 50

Rheumatology and Orthopedic ClinicsAtkinson et al66 34 Orthopedic clinic referrals Low back pain �6 mo 21.6Forrest and Wolkind67 50 Rheumatology clinic Low back pain 46Tilscher and Bogner68 53 Orthopedic patients Axial pain 89

Dental ClinicFeinmann69 93 Dental clinic Facial pain 35Lesse70 225 Facial pain patients Facial pain 100Lascelles71 93 “Face pain” clinic Facial pain 100 (Atypical)

Gynecology ClinicMagni et al72 29 Laparoscopy patients Pelvic pain �6 mo 17.2Walker et al73 100 Laparoscopy patients Pelvic pain �3 mo 12 (32 Lifetime)

Primary Care Clinics and Population-Based StudiesLove74 68 Private practice clinics Low back pain �6 mo 25Carroll et al75 1131 Population based Spinal pain 22Holroyd et al76 245 General population Chronic tension headache 28.6Kroenke et al36 1000 Primary care Multiple pain conditions 34-46Lamb et al77 408 Community women older than 65 y Knee pain 15.4-19.1Magni78 64 Factory workers Low back pain 4.7Magni et al79 3023 Population based Arthritis history 18Magni et al80 2341 Population households Chronic pain 16.4Von Korff et al81 1500 HMO enrollees Common pain conditions 5.9-10.7Wells et al82 2500 HMO and solo practice Somatic pain 35

Abbreviation: HMO, health maintenance organization.




pression are more difficult to de-tect than more severe and blatantcases, and patients with milder casesare more likely to present to pri-mary care providers than to psychia-trists.

Few studies focused on howpain plays a role in depression treat-ment considerations. For example,patients often attribute their pain-ful physical symptoms to an under-lying medical illness and want treat-ment for their pain. Health careproviders frequently accept the pa-tient’s request for pain treatment,while neglecting treatment for thepatient’s underlying depression.Fritzsche et al97 noticed that pa-tients with depression and pain wholacked psychological attribution totheir illness were offered less psy-chosocial treatment, experiencedworse outcomes, and received moremedications and physical therapy.

Only older studies addressedhow specific medication practiceswere influenced by pain in patientswith depression. For example, opi-oid analgesics were more com-monly prescribed than antidepres-sants in a sample of patients withdepression and chronic pain,98 andthere were no differences in seda-tive and antidepressant medica-tions used in chronic pain patientswith and without depression.48 As aresult, patients with chronic pain areat risk for polypharmacy, adversedrug events, and narcotic and/orbenzodiazepine dependence or ad-diction.99,100

DOES THE PRESENCE OF PAINAFFECT DEPRESSION

OUTCOMES?

Outcomes included depression se-verity and secondary measures suchas functional status, quality of life,health care costs and utilization, andtreatment efficacy. Unfortunately,most depression and pain studieshave either been cross-sectional orhave assessed the prognostic valueof depression for poor pain out-comes. Relatively few studies havespecifically addressed how the pres-ence of pain affects depression out-comes. Most work in this area hasbeen performed by Von Korff et al81

showing that the presence of up to5 different pain complaints (abdomi-

nal pain, headache, back pain, chestpain, and facial pain) is associatedwith increased symptoms of depres-sion. Further study demonstratedthat progressive pain severity at base-line was associated with poor de-pression outcomes, including moresevere depression, more pain-related functional limitations, worseself-rated health, higher unemploy-ment rate, more frequent use of opi-oid analgesics, and more frequentpain-related doctor visits (at base-line and 1-year follow-up).101 Inter-ference with daily activities due topain, the number of days in pain(within a 6-month period), and thediffuseness of pain (or number ofpain sites) also predicted the sever-ity of depression.102 Unimprovedback pain at short-term (7-week)and long-term (2-year) follow-upwas associated with significantlymore depressive symptoms andchronic depression when com-pared with patients whose back painimproved.101,103,104 Over the longterm, improvement in pain symp-toms was associated with a de-crease in depressive symptoms tonearly normal.81

When evaluated by changes inphysical symptoms, psychiatricsymptoms, and functional out-comes, patients without painfulphysical symptoms were found tohave better depression outcomes.105

In a sample of 217 patients with de-pression, pain was experienced onmore than half the days over a3-month period, producing 16 dayswhen usual activities were cur-tailed, 4 days missed from school orwork, and at least 1 visit with a phy-sician or clinical nurse.106 Retrospec-tive studies suggest that patients withdepression have significantly moreclinic visits, phone calls to the clinic,and hospitalizations for pain-related symptoms in the months lead-ing up to a diagnosis of depres-sion.107,108 A population-based studyfound that persons with depressionand concomitant pain initiated 20%more visits to medical providers andtheir total medical costs were higherthan persons with depression butwithout pain.109 Although some stud-ies suggest that patients with depres-sion and comorbid chronic low backpain respond just as well (eg, fewerdepression symptoms) to antidepres-

sants and cognitive behavioraltherapy as depressed patients with-out back pain, little is known abouthow or if pain complicates depres-sion outcomes.110,111 Bair et al21 sug-gest that baseline pain reduces thebenefits of antidepressant therapy at12 weeks in terms of depression andother quality-of-life outcomes, butmore prospective studies are neededto better quantify this.

Thegoalofdepressiontreatmentis complete symptom resolution orremission. Lingering physical symp-toms inpatientswithdepressionmayprevent patients from achieving re-mission of their depression. Cur-rently, up to 70% of patients respondto treatment but fail to achieve com-pleteresolutionoftheiremotionalandphysical symptoms.112,113 A recentclinical study114 found that 76% ofcompliantdepressedpatientswithlin-gering symptoms of depression re-lapsedwithin10months.Of thesepa-tients who experienced lingeringsymptoms, 94% had mild to moder-ate physical complaints.114

DOES THE PRESENCEOF DEPRESSION AFFECT

CLINICAL OUTCOMESIN PATIENTS TREATED

FOR PAIN?

We identified 22 studies* that ad-dressed how depression or depres-sive symptoms affect outcomes inpatients with pain (Table 3). Tenof the studies were based in man-aged care or other primary care set-tings, 6 in pain and/or specialty clin-ics, 4 were population-based, 1 studywas conducted at a worksite, and 1in surgical patients. The most com-mon pain condition examined waslow back pain. Depression was as-sociated with an array of poor painoutcomes and worse prognosis. Pa-tients with pain and comorbid de-pression experienced more paincomplaints,89 more intense pain,77

more amplification of pain symp-toms,82 and longer duration ofpain.116 Unfortunately patients withboth conditions were more likely tohave persistent pain116,120,123,125 andnonrecovery.120 Future episodes ofpain, such as low back pain, chest

*References 34, 35, 55, 67, 76, 77, 82, 89,103, 115-127.




pain, headache, and musculoskel-etal complaints were predicted by thepresence of depression.34,35,124,127

Functional limitations (eg, lim-ited mobility, activity restrictions)

and resulting disability, such as daysin bed ill and hospitalizations, wereincreased in patients with pain anddepression.77,82,89,116,117 Similarly, de-pression and pain produced addi-

tive impairments in social function-ing,76,82 higher unemploymentrates,42,55,67,118 and diminished pa-tient satisfaction.103 Engel et al119

showed that increased depressive

Table 3. Effect of Depression on Patients With Pain

SourceNo. of

Patients Setting SampleDepression

Diagnostic Tool Pain Measure Comments

Betrus et al89 237 Nursing clinic Women treated forphysicaldisorder

SCL-90 Health history ↑Physical complaints, ↑disability,↑functional limitations, ↑use of healthcare services

Blanchard et al115 91 Psychologydepartment

Chronic headaches BDI Headache index Depression associated with lessimprovement in headache index

Burton et al116 252 Primary care Low back pain Modified ZDI MPQ Persistent pain symptoms, functionalimpairment

Cherkin et al103 219 Primary care Low back pain(initial episode)

“SCL-6” “Symptomsatisfaction”

Depression associated with poor outcomeat 7 wk and at 1 y

Croft et al35 4501 Generalpopulation

Low back pain GHQ Record review,pain survey

Psychological symptoms predict later onsetof low back pain

Dionne et al117 1213 HMO Back pain inprimary care

SCL-90-R Telephoneinterview

Depression was one of the strongestpredictors of long-term functionallimitations

Dolce et al118 63 Pain managementprogram

Chronic pain BDI Pain scale(0-10)

Depression predicted less return to work

Engel et al119 1059 Primary care Back pain SCL-90R CPSP ↑Depressive symptoms associated with �2back pain follow-up visits, �2 back painradiographs, �8 pain medication refills,↑total costs

Forrest andWolkind67

50 Rheumatologyclinic

Low back pain Middlesex Survey Health history Depressed group more likely to have “poorresponse”

Gureje et al120 3197 Primary care Persistent painsyndromes

CIDI Pain survey Depressive disorder at baseline marginallypredicted pain nonrecovery, predictedonset of persistent pain

Holroyd et al76 245 Generalpopulation

Chronic tensionheadache

BDI/PRIME-MD Headacheassessment

Daily headaches with depression frequentlyimpaired on one SF20 subscale

Kerns andHaythorn-thwaite121

131 Pain rehabilitationprogram

Chronic pain BDI MPQ No difference in depressed andnondepressed group in pain outcomes

Kramlinger et al55 100 Pain center Chronic painconditions

Hamilton Scale Pain scale(0-10)

More work loss in patients with pain anddepression

Lamb et al77 769 Communitywomen �65 y

Knee pain GDS WOMOI Depression ↑pain and effect on walkingability/limited mobility

Leino and Magni34 607 Metal plant Employees withmusculoskeletalsymptoms

Depressivesymptoms

Musculoskeletalsurvey

Depressive symptoms predict futuremusculoskeletal symptoms and findingsin men

Painter et al122 50 Pain center Chronic painconditions

MMPI Pain scales Depression more common in treatmentfailure group

Potter and Jones123 45 Primary care Musculoskeletalpain (newonset)

GBQ MPQ Depression on screening was associatedwith development of chronic pain

Power et al124 571 British birthcohort

Low back pain “MalaiseInventory”

Back painhistory

Depression doubled risk of incident lowback pain

Reis et al125 219 Family practice Low back pain(new onset)

3-item DepressionTool

Low back paincomplaint

Depression was strong predictor ofchronicity

Taenzer et al126 40 Surgical patients Gallbladdersurgery

BDI Postoperativepain

Significant correlation between depressionscore and postoperative pain

Von Korff et al127 803 HMO enrollees Common painsymptoms

SCL-90R Pain interview Moderate to severe depressive symptomspredicted new onset of chest pain andheadache; nonsignificant onset rates forback pain, abdominal pain, and TMD pain

Wells et al82 2554 HMO and solopractice

Patients withdepressivesymptoms

Depressivesymptoms/DIS

Survey Major depression causes ↑ pain symptoms,↑ functional disability, and ↓ socialfunction

Abbreviations: BDI, Beck Depression Inventory; CIDI, Composite International Diagnostic Interview; CPSP, Chronic Pain Scale and Persistence; DIS, DiagnosticInterview Schedule; GBQ, Goldberg’s Brief Questionnaire; GDS, Geriatric Depression Scale; GHQ, General Health Questionnaire; HMO, health maintenance organization;MMPI, Minnesota Multiphasic Personality Inventory; MPQ, McGill Pain Questionnaire; PRIME-MD, Primary Care Evaluation of Mental Disorders; SCL-6, SymptomChecklist–6 items; SCL-90, Hopkins Symptoms Checklist, 90 items; SCL-90R, SCL-90 Revised; SF20, 20-Item Short-Form Health Survey; TMD, temporomandibulardisorder; WOMOI, Western Ontario McMaster Osteoarthritis Index; ZDI, Zung Depression Index; ↑, increased; ↓, decreased.




symptoms in patients with low backpain also increased health care uti-lization. Higher depressive symp-toms were associated with more pri-mary care follow-up visits for backpain, more back pain–related radio-graphs, more pain medication re-fills, and higher total costs.89 “Pooroutcomes” were observed at short-term (7 weeks) and long-term (1year) follow-up.103 In surgical pa-tients, those with higher preopera-tive depression scores experiencedgreater postoperative pain.126

Some studies35,116 and a litera-ture review by Linton128 have sug-gested that depression has a greaterimpact than other clinical factors onoutcomes, especially functional im-pairment, in patients with pain, andthat neglecting to treat the depres-sion accounts for some of the paintreatment failures.38,52 Patients withdepression and chronic pain wereless likely to comply with pain re-habilitation and thus more likely torelapse following treatment.121,122 Al-though most studies (Table 3) sup-port the finding that patients with

pain and depression have pooreroverall response to treatment thanpain patients without depression, afew did not report such a relation-ship.55,121,129,130

IS ANTIDEPRESSANTTREATMENT FOR PAINFUL

SYMPTOMS AND COMORBIDDEPRESSION EFFECTIVE?

Feinmann131 has previously re-viewed studies that reported pain re-lief associated with depression symp-tom rel ief . We identi f ied 22studies6,71,132-151 that examined anti-depressant efficacy for treating painsymptoms and subsequent depres-sion response (Table4). We did notinclude studies of symptom syn-dromes (eg, fibromyalgia, irritablebowel syndrome, migraine head-aches) or studies excluding pa-tients with depression or organicpain (eg, diabetic neuropathy, can-cer pain) because these conditionshave been reviewed previously, andantidepressants were found to be ef-fective.18-20,152,153 The primary out-

come in all the studies in Table 4 waspain relief or other pain outcomes,while depression symptom relief wasone of the secondary outcomes.Sample sizes were relatively small,ranging from 14 to 253. Only 4 stud-ies6,132,137,141 were conducted in a pri-mary care setting, with the remain-der situated in pain, psychiatric, andspecialty clinics. The interventionarm of each selected study usuallyinvolved tricyclic antidepressants,and only 4 studies involved selec-tive serotonin reuptake inhibitors(SSRIs)135,138,143,145 to assess pain anddepression. While most of the stud-ies demonstrated improvement inboth pain and depression symp-toms, a few of the studies132,142,147

failed to show symptom relief.Whether SSRIs improve painfulsymptoms associated with depres-sion is unsettled. Most studies wereuncontrolled, of short duration (av-eraging 9 weeks), and used dosesthat were subtherapeutic for ad-equate depression treatment.

Anecdotal reports note thatwhen depression is successfully

Table 4. Effect of Antidepressants on Pain and Comorbid Depression Outcomes

SourceNo. of

Patients Setting Sample Medication(s)

Outcome

Pain Depression

Alcoff et al132 50 Family practice Chronic low back pain Imipramine No change No changeBlumer et al133 104 Pain clinic Chronic pain Amitriptyline, imipramine,

loxapine, carbamazepine57% Improved Improved

Cannon et al134 60 National Institutes ofHealth

Chest pain Imipramine Improved No change

Dickens et al135 98 Rheumatology clinic Low back pain Paroxetine, placebo No difference No differenceFeinmann et al136 93 Oral surgery clinic Psychogenic facial pain Dothiepin Improved ImprovedGringras137 55 General practice Rheumatic pain Tofranil Improved ImprovedGourlay et al138 20 Pain clinic Chronic pain Zimelidine No difference No differenceHameroff et al139 30 Pain clinic Low back pain, cervical pain Doxepin Improved ImprovedHameroff et al140 60 Pain clinic Low back pain, cervical pain Doxepin Improved ImprovedHill and Blendis141 27 Outpatient practice “Nonorganic” abdominal

painAmitriptyline, imipramine 100% Improved 100% Improved

Jenkins et al142 44 Rehab unit Low back pain Imipramine No change No changeJohansson and

von Knorring14340 Pain clinic Chronic pain Zimelidine, placebo Improved No difference

Lascelles71 40 “Face pain” clinic Atypical facial pain Phenelzine 75% Improved ImprovedLindsay and Wyckoff6 116 Private practice “Recurring benign pain” Amitriptyline, imipramine,

desipramine, doxepin83% Improved Not mentioned

Loldrup et al144 253 Multisite Chronic idiopathic pain Clomipramine, mianserin No change 75% ImprovedManna et al145 40 Psychiatry clinic Chronic tension headache Fluvoxamine, mianserin Improved ImprovedMerskey and

Hester14630 Psychiatry clinic Various pain syndromes “Antidepressants,”

phenothiazines, antihistamines70% Improved Improved

Pilowsky et al147 32 Pain clinic Pain of unknown origin Amitriptyline No change No changeSherwin148 14 Neurology clinic Headache Amitriptyline, perphenazine 70% Improved ImprovedSingh and Verma149 60 Psychiatry clinic Pain, no etiology Amitriptyline, imipramine 80% Improved ImprovedTyber150 34 “Private practice” Shoulder pain Amitriptyline, lithium Improved ImprovedWard et al151 36 Newspaper ad

respondentsChronic back pain Doxepin, desipramine 50% Improved 70% Improved




treated, the patient’s somatic symp-toms, particularly pain complaints,are also relieved.59,88 In a 6-weekclinical trial comparing fluoxetinewith placebo, outpatients with ma-jor depression who were treated withactive medication had significant im-provements in functional health, in-cluding painful symptoms, com-pared with the placebo group.154

However, a trial investigating a col-laborative management program fordepression vs usual care showed sig-nificantly fewer somatization symp-toms at follow-up but no signifi-cant intervention effect on painsymptoms.155 A relatively recentmeta-analysis153 of antidepressantuse in treating symptom syn-dromes and unexplained symp-toms found that symptom improve-ment did not usually correlate withdepression response in the studieswhere both pain and depressionwere assessed. Only a third of stud-ies showed improvement in physi-cal symptoms in concert withdepression response. Similarly,a review of cognitive-behavioral

therapy for somatic symptomsshowed an effect on somatic symp-toms that appeared, at least in part,independent of an effect on psycho-logical distress.156 Several studieshave examined the use of SSRIs inpain syndromes such as diabeticneuropathy and fibromyalgia, butfew of these have assessed changesin both pain and depression.157 Onthe other hand, Ward et al32 re-ported that the degree of depres-sion improvement correlated withthe amount of pain relief. Otherstudies have suggested that the com-bination of antidepressants and cog-nitive behavioral therapy may be ef-fective in treating patients with bothchronic pain and depression.6,44,47

WHAT ARE THE COMMONBIOLOGICAL PATHWAYS FORDEPRESSION AND PAIN, AND

WHAT ARE THEIMPLICATIONS FOR

TREATMENT?

The biochemical theory of depres-sion posits that depression is the re-

sult of a neurochemical imbalance ora functional deficiency of key neu-rotransmitters, the monoamines:serotonin, norepinephrine, and do-pamine. A common theory holds thatdepression and painful symptoms fol-low the same descending pathwaysof the central nervous system. Eightstudies described the biological linkbetween depression and pain. Al-though nociceptive fibers transmit-ting pain signals from the peripheryof the body through the dorsal hornto the medulla, midbrain, hypothala-mus, thalamus, limbic cortical areas(anterior cingulate and insular cor-tex), somatosensory cortex, and pos-terior parietal cortex have been care-fully mapped, there is an increasinginterest in the neuroanatomy of a de-scending system of pain modula-tion.158 The increasing knowledgeabout this system allows scientistsand physicians to better understandmechanisms of pain modulation viamedications as well as psychologi-cal mechanisms such as expecta-tion, attention and distraction, andnegative and positive affect.

The periaqueductal gray (PAG)is a key anatomic structure in the painmodulation system.158,159 As shown inthe Figure, the PAG is an anatomicrelay from limbic forebrain and mid-brain structures to the brainstem. Theamygdala, hypothalamus, and fron-tal neocortex all send fibers to thePAG, which connects with relay sys-tems in the pons and medulla.159

These relay systems contain seroton-ergic neurons such as those in therostral-ventromedial medulla (RVM)as well as noradrenergic neurons suchas those in the dorsolateral pontinetegmentum (DLPT).160 The RVMsends projections to the dorsal horndirectly, whereas the DLPT affectsdorsal horn neurons indirectly by itsprojections to the RVM as well as hav-ing direct connections (inhibitoryonly) to the dorsal horn. The RVMhas 2 types of cells important in painperception: “on cells,” which facili-tate pain transmission; and “off cells,”which inhibit pain perception.158

The on and off cells in the RVMthrough data transmitted from thelimbic forebrain and other struc-tures transmitted through the PAGmay amplify or dampen pain im-pulses transmitted from the periph-ery. Activation of the RVM off neu-

Transmission

F

CxSS

Cx

Midbrain

Medulla

Spinal Cord

Hyp

ReticulothalamicSpinothalamic

Thalamus

Modulation

1

On the left is illustrated the transmission system for nociceptive messages. Noxious stimuli activate thesensitive peripheral ending of the primary afferent nociceptor by the process of transduction (1). Themessage is then transmitted over the peripheral nerve to the spinal cord, where it synapses with cells oforigin of the 2 major ascending pain pathways, the spinothalamic and spinoreticulothalamic. Themessage is relayed in the thalamus to both the frontal cortex (F Cx) and the somatosensory cortex(SS Cx). On the right is the pain modulation network. Inputs from the frontal cortex and hypothalamus(Hyp) activate cells in the midbrain, which control spinal pain transmission cells via cells in the medulla.(Figure reproduced from Fields HL. Pain. New York, NY: McGraw-Hill; 1987, with permission.)




rons or the DLPT neurons viaelectrical stimulation depresses theactivity of nociceptive neurons in thespinal dorsal horn.158,160 These bidi-rectional on/off systems determinevigilance to either external threatsor sensations coming from inside thebody.158,161 Limbic structures, thePAG, and these on and off cells de-termine affect and attention to pe-ripheral stimuli. Normally, this sys-tem has a modulatory effect, tendingto dampen signals coming in fromthe body so that these signals aresuppressed, allowing attention to befocused on more important eventsoutside of the body.159,161 However,with depletion of serotonin and nor-epinephrine, as occurs in depres-sion, this system may lose its modu-latory effect such that minor signalsfrom the body are amplified, andmore attention and emotion are fo-cused on them. This explanationmay tell us why patients with de-pression describe multiple painsymptoms and why their pain is of-ten associated with increased atten-tion, focus, and negative affect.

Studies have shown that thePAG and relay sites in the mid-brain, medulla, amygdala, and dor-sal horn are rich in endogenous opi-oids such as enkephalins.158,162

Experimental studies have shownthat morphine applied at any of theabove sites of the descending painmodulatory system (limbic cortex,midbrain, medulla, or dorsal horn)blocks peripheral pain signals.158,162

Serotonin and norepinephrine givenintrathecally also block pain sig-nals.158,160 By increasing levels ofserotonin and norepinephrine avail-ability in key brain areas, antide-pressants also have effects on modu-lating pain signals.163 This effect ofantidepressants may be greatest formedications that increase availabil-ity of serotonin and norepineph-rine.163

Studies have shown that brainregions involved in the generationof emotion (eg, the medial prefron-tal, insular, and anterior temporalcortex, hypothalamus, and amyg-dala) send many projections tobrainstem structures involved inpain modulation (PAG and RVM).158

Studies have shown that the activ-ity of the anterior cingulate gyrus in-creases with peripheral pain stimuli,

such as heat applied to the skin, butit also has increased activity whenwarm stimuli are applied if the pa-tient is expecting hot stimuli.158,164,165

Negative anticipation causes keybrain areas to activate, and the sub-ject then appears to focus, attend to,and rate the pain stimuli as more se-vere. Distraction from pain signalsin experimental pain has been shownin other experiments to decrease ac-tivation of PAG and decrease painperception.164,165 Also, opiates ex-cite off cells and inhibit on cells.These 2 effects help suppress painsignals. Perhaps these experimentssuggest how depression, which is as-sociated with negative expectan-cies, may amplify pain signals by ac-tivating brain structures such as theanterior cingulate gyrus. Depres-sion is also associated with deple-tion of serotonin and norepineph-rine, which may decrease themodulatory effect of this descend-ing pain system.

CONCLUSIONS

Several key themes emerged fromour review of the relationship be-tween depression and pain. First ofall, the prevalence of pain in a de-pressed sample and the prevalenceof depression in a pain sample arehigher than the prevalence rateswhen the conditions are individu-ally examined. On average, 65% ofpatients with depression experi-ence one or more pain complaints,and depression is present in 5% to85% (depending on the study set-ting) of patients with pain condi-tions. Depression is most prevalentin pain, psychiatric, and specialtyclinics vs population-based or pri-mary care studies.

Second, the presence of painnegatively affects the recognition andtreatment of depression. Depres-sion is often underrecognized andthus frequently undertreated. At least75% of primary care patients withdepression present with physicalcomplaints exclusively92,166 and sel-dom attribute their pain symptomsto depression or other psychiatric ill-ness. These physical complaints maybe due to amplification of chronicphysical disease and remain medi-cally unexplained after extensiveworkup. As a result, providers fre-

quently assess for physical causes ofpain and treat medically instead ofexploring the pain symptoms in abroader, biopsychosocial context.

Primary care providers shouldrecognize that pain is a commonsymptom of depression, that depres-sion and painful conditions fre-quently coexist, and that evalua-tion and treatment of both areimportant. At least in primary caresettings, the typical depression pre-sentation is complicated more of-ten by painful symptoms and physi-cal complaints than emotionalsymptoms of sad mood or anhedo-nia. The patient who presents “look-ing depressed” is not difficult to rec-ognize for most providers but mayrepresent the minority of patientswith depression seen in primary care.

Recognition would likely be im-proved by screening for depressionin any patient with unexplained painor unexplained exacerbation of astable painful condition. Often pa-tients are referred to specialists withexpertise in treating pain or exper-tise in treating depression rather thanto a provider who is comfortabletreating both. Primary care physi-cians seem to be in the best posi-tion to manage both conditions butmay lack the knowledge and expe-rience to tackle this difficult butcommon clinical situation. Also, theshort visit times, inadequate reim-bursement, and competing de-mands on the primary care physi-cian can interfere with optimalmanagement of these complex con-ditions.167,168

Different aspects of pain nega-tively affect several depression out-comes. Increasing pain severity, painthat interferes with daily activities,frequent pain episodes, diffuse pain,and pain that is refractory to treat-ment are all associated with more de-pressive symptoms and more se-vere depression. Additionally, aspain severity worsens, other depres-sion outcomes such as functionallimitations, health-related quality oflife, and work function are ad-versely affected. Pain with comor-bid depression also appears to be ad-ditive in terms of an increasednumber of medical visits and higherhealth care costs. The prognosis ofcomorbid depression and pain ispoor compared with the prognosis




for individuals with depression with-out pain.169 What is not clear iswhether patients with depressionand pain are less responsive to usualdepression management than thosewith depression alone.

Our literature review estab-lishes the reciprocal nature of the de-pression-pain relationship. Depres-sion complicates the management ofpatients with pain and is associatedwith poorer outcomes. In patientswith pain, depression is associatedwith more pain complaints, greaterpain intensity, longer duration ofpain, and greater likelihood of non-recovery. Additive impairments insocial function, work function, andfunctional limitations (eg, limitedmobility and restricted activity) areseen when depression and pain co-exist. Depression also predicts in-creased health care utilization,poorer adherence to treatment,worse patient satisfaction, and fu-ture episodes of pain.

Most studies that examined an-tidepressant treatment of pain con-ditions suggested that pain and de-pression symptoms improvedsimultaneously, with the caveats thatmost of these studies were uncon-trolled, of short duration, and de-signed more to measure pain re-sponse. Tricyclic antidepressantshave been the predominant therapyevaluated. Preliminary data sug-gest that some of the newer antide-pressants, including agents that acton several receptors (eg, norepi-nephrine and serotonin), may beuseful in chronic pain.170-173 How-ever, larger clinical trials on non–tricyclic antidepressants in pa-tients with comorbid depression andpain are needed. Unfortunately, veryfew depression treatment trials haveassessed whether pain improves inconcert with depression symptomsand whether greater improvement inpain or depression relates to greaterimprovement in the other condi-tion. Despite the promising find-ings that depression and pain re-spond to antidepressant therapy,many patients are treated primarilywith pain-relieving medications thathave little intrinsic antidepressanteffect.

Recent research has providedevidence of a central pain modula-tion system that can either dampen

or amplify nociceptive signals fromthe periphery. Both serotonin andnorepinephrine have been shown todampen peripheral pain signals. Thisexplains how depression, which isassociated with a dysregulation ofthese key modulating neurotrans-mitters along a shared pathway, maycontribute to the frequent presenceof painful symptoms. Thus the de-crease in one or both of these neu-rotransmitters may increase periph-eral pain messages and affect howantidepressants that increase theseneurotransmitters decrease pain sig-nals.

In summary, the combinationof depression and pain is associ-ated with worse clinical outcomesthan either condition alone. Thus,a treatment model that incorpo-rates assessment and treatment ofboth depression and pain seems nec-essary for more optimal outcomes.More research is needed to deter-mine if alleviation of pain helps thepatients’ depressive symptoms and,likewise, whether relief of depres-sive symptoms improves pain and itsrelated morbidity. Inattention to paincan cause refractoriness to depres-sion treatment and not addressingdepression can preclude successfulpain treatment.Dual therapy trialsare needed to see if depression andpain outcomes can be improved withattention to their comorbidity.

Accepted for publication January 31,2003.

From the Regenstrief Instituteand Department of Medicine, Indi-ana University School of Medicine(Drs Bair and Kroenke), and Eli Lillyand Company (Ms Robinson), India-napolis, Ind; and the Department ofPsychiatry and Behavioral Sciences,University of Washington MedicalCenter, Seattle (Dr Katon).

This project was supported inpart by grant T-32 PE15001 from theHealth Resources and Service Admin-istration and by funding from Eli Lillyand Company, Indianapolis, Ind.

Corresponding author and re-prints: Matthew J. Bair, MD, MS,Richard L. Roudebush VA MedicalCenter, Mail Code 11-H, 1481 W 10thSt, Indianapolis, IN 46202 (e-mail:[email protected]).

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