COMPLEX MEDICAL-PSYCHIATRIC ISSUES (MB RIBA, SECTION EDITOR)

Pain and Depression: An Integrative Reviewof Neurobiological and Psychological Factors

Jenna Goesling & Daniel J. Clauw & Afton L. Hassett

Published online: 10 November 2013# Springer Science+Business Media New York 2013

Abstract The comorbidity of pain and depression has beenwell established in the literature and is associated with agreater burden to the individual and society than either con-dition alone. The relationship between pain and depression isquite complex and multiple factors must be considered whentrying to disentangle the pain-depression link including sharedneurobiology, precipitating environmental factors and cogni-tive influences. This article aims to provide an overview of theleading neurobiological and psychosocial theories that haveadvanced our understanding of the link between pain anddepression. To this end we describe the shared neurobiologicalmechanisms in the brain thought to explain the overlap andconsider psychological processes and how they inform acognitive behavioral model. The article also provides an over-view of the evidence based treatment for comorbid pain anddepression.

Keywords Chronic pain .Depression . Pain-depression link .

Treatment . Cognitive behavioral therapy . Neuromodulators

Introduction

Pain and depression are two of the most critical public healthissues facing health care providers today. The recent Instituteof Medicine (IOM) report, Relieving Pain in America,stressed the urgent need to address the costs of chronic pain:100 million Americans suffer from chronic pain, 200 milliondays of work are lost, and the economic costs are estimated tobe upwards of /635 billion dollars [1]. Similarly, it is estimat-ed that depression affects approximately 350 million peopleglobally [2] and 16.2 % of Americans at some point in theirlifetime [3]. Depression is one of the leading causes of dis-ability worldwide [4] and is a significant contributor to in-creased medical costs [5] and economic burden [2]. Unfortu-nately, pain and depression frequently coexist and this comor-bidity is associated with a greater burden to the individual andsociety than either condition alone [6, 7].

The comorbidity of pain and depression has been wellestablished in the literature [8, 9]. On average between 30-60 % of pain patients report comorbid depression [9]. Addi-tionally, the prevalence of a lifetime history of major depres-sion or other mood disorders is even higher in chronic paincohorts [10]. Among patients being treated for depression,comorbid pain conditions are also common [7, 9, 11]. It isestimated that around 50 % of patients with depression reportexperiencing some physical pain symptoms [12]. The conse-quences of this overlap are also important to consider. Forinstance, when patients with pain have comorbid depression,they have greater pain, a worse prognosis, andmore functionaldisability [13]. Additionally, chronic pain patients with co-morbid depression have higher health care costs compared topain patients who do not have depression [5, 14]. In sum, theextensive literature leaves little question that pain and depres-sion often present together and when they do co-occur the costis significant.

Currently, the most widely accepted interpretation of therelationship between pain and depression is that it is bidirec-tional [15••, 16]. That is, not only does the presence of one

This article is part of the Topical Collection on Complex Medical-Psychiatric Issues

J. Goesling (*)Department of Anesthesiology, Back & Pain Center, University ofMichigan, Burlington Building 1, Suite 100, 325 E. EisenhowerParkway, Ann Arbor, MI 48108, USAe-mail: jennagoe@med.umich.edu

D. J. Clauw :A. L. HassettDepartment of Anesthesiology, University of Michigan HealthSystem, Domino’s Farms, Lobby M, 24 Frank Lloyd Wright Dr.,PO Box 385, Ann Arbor, MI 48106, USA

D. J. Clauwe-mail: dclauw@med.umich.edu

A. L. Hassette-mail: afton@med.umich.edu

Curr Psychiatry Rep (2013) 15:421DOI 10.1007/s11920-013-0421-0

often lead to the development or exacerbation of the other, buta change in severity in one is also likely to produce a change inthe other [15••]. However, an ongoing debate exists in thefield as to whether depression is an antecedent to or conse-quence of pain. One argument for an antecedent model is thatdepression leads to changes (e.g., neurobiological, cognitive/behavioral,) that would cause increased vulnerability to painin the future. There are data to support this conclusion. Forexample, in a community sample of people without pain,higher levels of psychological distress were associated withsubsequently developing chronic widespread pain [17]. Asomewhat stronger case has been made for depression as aconsequence of pain [16]. In a recent longitudinal study thatexcluded participants with a history of depression or anxiety,researchers found that baseline pain symptoms were a riskfactor for developing depression [18]. McBeth and colleaguesalso found an association between chronic wide spread painand future distress [19]. Interestingly, when they controlled forbaseline comorbidities (e.g., somatic symptoms, fatigue),baseline chronic wide spread pain no longer predicted futuredistress, suggesting that it may be the interaction between painand psychosocial factors that explains the true nature of theassociation.

The relationship between pain and depression is complexand multiple factors must be considered when trying to dis-entangle the pain-depression link, including shared neurobi-ology, genetics, precipitating environmental factors and cog-nitive influences. The primary aim of this paper is to providean overview of the leading neurobiological and psychosocialtheories that have advanced our understanding of the linkbetween pain and depression. To that end, we describe theshared neurobiological mechanisms in the brain thought toexplain the overlap. Additionally, we consider psychologicalprocesses and how they inform a cognitive behavioral modelfor the link between pain and depression. The second aim ofthe paper is to review the current research on evidence-basedtreatment for comorbid pain and depression.

Why Pain and Depression are Associated:A Neurobiological Perspective

Brain Regions Associated with Physical and PsychologicalPain

To understand why pain and depression are associated, it isnecessary to consider how they are similar (and different) at aneurobiological level. Physical pain is processed via a complexmultidimensional pain system with distinct areas in the brainfor processing the sensory-discriminative dimension of pain(location) and the affective-emotional dimension of pain(suffering). Brain regions associated predominantly with thesensory-discriminate component of physical pain include the

somatosensory cortices (S1 and S2) and the dorsal posteriorinsula [20]. On the surface, psychological pain (e.g., grief,social exclusion, sadness) seems different from physical painbecause it does not involve a noxious bodily stimulus. How-ever, both types of pain signal threat and consequently activateneural mechanisms to help assess and deal with that threat.Improvements in neuroimaging have enabled researchers toidentify several structural regions that are associated with bothphysical pain and psychological pain. The nociceptive pathwayfor psychological pain involves several of the same brainstructures that process the affective-emotional component ofphysical pain [21–23]. A recent review of the literature [21]revealed that the brain regions most often associated withoverlap between the affective-emotional aspect of physical painand psychological pain were the anterior insula, prefrontalcortex, anterior cingulate cortex, and thalamus. Additionalresearch shows overlap in the amygdala and hippocampus [24].

Shared Neurotransmitters and the Mechanisms of Actionof Pharmacological Treatment

Pain processing and mood are both controlled by commonneurotransmitters such as serotonin, norepinephrine, gluta-mate and GABA. Serotonin (binding at the 5HT1 receptors)and norepinephrinemediate pain inhibition, at least in part, viatheir effect on the descending pain pathways of the centralnervous system. Similar neurotransmitter abnormalities existand provide further support for a neural basis for the associ-ation between pain and depression. If pain and depressionshare neurotransmitters that are part of an overlapping painsystem, it follows that they should respond to similar pharma-cological treatments. Tricyclic compounds (TCAs), serotoninnorepinephrine reuptake inhibitors (SNRIs), and selective se-rotonin reuptake inhibitors (SSRIs) are most commonly re-ferred to as antidepressants because they were initially devel-oped to treat depression. However, this label can be somewhatmisleading because these drugs’mechanisms of action are notlimited to alleviating symptoms of depression. For example, itis becoming increasingly clear that highly selective serotoninreuptake inhibitors that do not also affect norepinephrinelevels (e.g., citalopram) are not analgesics. Therefore, it ismore accurate to think of these according to their mechanismof action and not as antidepressants per se .

Numerousmeta-analyses and review articles have conclud-ed that certain antidepressants have at least a moderate anal-gesic effect and are recommended as a first line of treatment insome pain conditions [25–27]. Researchers have proposedseveral possible explanations for the analgesic effects of anti-depressants including direct effects on pain processing (e.g.,modulation of the descending pain pathway) [28], reductionof depression symptoms, and placebo. Results from RCTssuggest that analgesic effects are found across a range ofchronic pain conditions and the effect appears to be

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independent of a reduction in the symptoms of depression [28,29]. In patients with diabetic peripheral neuropathy with andwithout depression, path analyses estimated that 90 % ofanalgesic effect of the Duloxetine (SNRI) was due to a directanalgesic effect [30]. In fibromyalgia patients with comorbiddepression, the direct effect of improvement in pain due toanalgesic effect was 68.7 % and 31.3 % of improvement inpain was due to indirect improvements in symptoms of MajorDepressive Disorder (MDD) [28]. The doses of these drugsthat are necessary to treat depression and pain are oftendifferent as well, probably because norepinephrine is beingshown to have relatively greater importance than serotonin.For example, lower doses of TCAs are needed for pain reliefthan depression [31], whereas higher doses of SSRIs areneeded [31] to treat pain than depression (perhaps becauseolder SSRIs become more noradrenergic at these higherdoses). In conclusion, the data on TCAs and SNRIs furthersupport the similarity between pain and depression at a neu-rological level.

Psychophysiological Data

One of the major advances in the last several years has been anincrease in research aimed at identifying objective measures ofpain. Experimentally induced pain increases neural activityacross a network of brain structures and provides a valuablemethodological approach for assessing the sensory and affec-tive dimensions of pain. In healthy participants, researchershave identified somatic-specific regions in the brain (e.g.,ventrolateral thalamus, secondary somatosensory cortex, andthe dorsal posterior insula) using fMRI that were active duringthermal pain and responded to opioids [32••]. The authors ofthis work suggest this type of “neurological signature” mayserve as a marker for responsiveness to treatment [32••]. In anfMRI study that included patients diagnosed with fibromyal-gia with and without depression, administering a painful ex-perimental stimulus led to similarly augmented pain process-ing in both groups [24]. But the fibromyalgia patients withdepression had much more robust activations in brain regionsknown to be associated with the affective processing of pain-ful stimuli, such as the amygdala and anterior cingulate re-gions [24]. In contrast, another study by this same groupshowed that when fibromyalgia patients with and withoutcatastrophizing were given the same type of experimental painstimulus, those individuals with catastrophizing displayedmore neuronal activation in affective regions as well as areasthat are thought to code for sensory intensity such as thesecondary somatosensory cortex [33].

Experimental pain testing also can be used to test hypoth-eses about the involvement of the central nervous system inorder to identify the underlying mechanisms that may in partexplain the high comorbidity of pain and depression. Diffusenoxious inhibitory control (DNIC or more recently termed

conditioned pain modulation) is an endogenous inhibitorypain system. When DNIC is activated, one nociceptive stim-ulus will cancel out other nociceptive stimuli. Several studiesusing experimental pain testing have demonstrated that pa-tients with fibromyalgia have deficits in DNIC. A recent studycompared patients with fibromyalgia and patients with MDDto see if a deficit in pain inhibition (i.e., diminished DNIC)was also present in depressed patients [34]. Pain inhibitionwas present in healthy controls and patients with MDD, butnot fibromyalgia patients. These results suggest that fibromy-algia is distinguishable from MDD on a core feature, specif-ically a deficit in pain inhibition. The authors hypothesizedthat deficits in serotonin and norepinephrine in MDD patientsmay not impact pain inhibition via this pathway. Interestingly,all theMDD patients in this study were taking antidepressants.In a subanalysis comparing fibromyalgia patients on antide-pressants to fibromyalgia patients not on antidepressants, thegroup on antidepressants did not have improved DNIC effi-ciency [34]. One possibility is that antidepressants are effec-tive for improving pain inhibition deficits in depressed pa-tients but not in fibromyalgia patients. In a similar study onfibromyalgia and DNIC, thermal pain stimuli were used tocompare depressed and nondepressed fibromyalgia patients[35]. Deficits in DNIC pain inhibition were more pronouncedin fibromyalgia patients who also had depression compared tofibromyalgia patients without depression. Importantly, nonde-pressed fibromyalgia patients still had deficits in DNIC, whichsuggests that regardless of depression, fibromyalgia is associ-ated with a deficit in pain inhibition. These results furthersupport the case for multiple processing networks.

Genetics

Hypotheses about the link between pain and depression havefocused on whether one causes the other. Perhaps an equallyimportant question is whether people have an underlying ge-netic vulnerability that causes individuals to be susceptible toboth pain and depression. Genetics research is still in the earlystages as many initial findings are contradicted by subsequentstudies, but there appear to be sets of genes controlling break-down or binding of neurotransmitters and cytokines involvedin the pathogenesis of both pain and depression that may alsocontribute to shared vulnerability to both sets of disorders.

Why Pain and Depression are Associated: Cognitive,Affective and Behavioral Factors

The perspective that pain and depression are highly comorbiddue to overlapping psychosocial factors is not new, but is stillcritical to consider. Many of the same cognitive and affectivefactors that increase the risk of developing depression and/orcontribute to poor outcomes are the very same factors found to

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be critical in pain populations. When considering patients withchronic pain, a cognitive-behavioral model poses that thoughtsdrive emotions and both of these factors, in turn, influencebehaviors. Thus, depression is a response to the consequencesof living with constant pain. That is, when a person has chronicpain, typically he/she becomes less involved in pleasurableactivities and experiences fewer social rewards and a dimin-ished enjoyment of life, which can eventually culminate indepression. However, the path from pain to depression is notinevitable and a number of psychosocial factors can mediatethis relationship. This is an extensive topic and a thoroughdiscussion is beyond the scope of this paper, thus we presenta few of the most important influencing variables.

Cognitive Factors

Reduced functioning and other consequences of living withpain can lead to thoughts of loss which negatively impactmood [36]. The different ways people with chronic painappraise their situation can have a profound impact on painand functioning. Numerous cognitive variables have beenshown to mediate the pain-depression association, such aspessimism, perceived locus of control, fear avoidance beliefs,self-efficacy, and perceived social support [37–42]. Perhapsthe best studied and potentially most relevant to the pain-depression relationship is catastrophizing. Catastrophizing isconsidered a cognitive error where one assumes the worstpossible outcome will occur [43]. It has been associated withpain and depression separately, and when they co-occur[44–46]. Depression and catastrophizing are related to greaterpain severity [47] and disability [46], conversely studies sug-gest that those who catastrophize their pain tend to feel pow-erless, fearful and even unworthy [48]; all processes thoughtto result in depression. Recent research supportive of thisnotion include a study evaluating depression in 669 olderadults with chronic pain which found that catastrophizingmediated the relationship between pain intensity and depres-sion [49]. Similarly, a German study using path analysis foranalyzing the data of 413 patients with back pain reported thatpain had no direct effect on depression when controlling forcognitive mediators which included catastrophizing [50].Thus, these data suggest that how someone with chronic painthinks could be the most important factor in the developmentof depression.

Affective Factors

The terms “affect” and “mood” are related but independent.Negative affect encompasses a broad spectrum of emotionalterms including, but not limited to sadness, fear, distress,hostility, anxiety, and shame. People with major depressivedisorder typically have high levels of negative affect, but noteverybody with high levels of negative affect will qualify for a

diagnosis of major depressive disorder, although such indi-viduals are likely at an increased risk [51]. Affect can becharacterized as trait (largely influenced by temperament) orstate (more dependent on external factors) yet, either way,negative emotions can predispose certain individuals withchronic pain to depression. Conversely, there is increasinginterest in resilience and the importance of positive affect inmental health and medical populations [52–55]. Positive af-fect is characterized by a general predisposition toward enthu-siasm, feelings of personal strength and determination. Higherlevels of positive affect have been associated with less pain,depression, pain catastrophizing and fatigue, and in somechronic pain populations (e.g., fibromyalgia) may better ac-count for poor outcomes than negative affect [51, 56, 57].Newer studies emphasize the proposition that both negativeaffect and positive affect have important relationships withclinical and experimentally induced pain [51, 58–60]. This hasdirectly been shown through experimental manipulations ofaffective states relevant to pain. For example, a recent exper-imental study showed that when pain is relieved negativeaffect is diminished and positive affect stimulated [61]. Thesestudies suggest that modifiable affective factors are intricatelyinvolved in the pain/depression relationship.

Behavioral Factors

There is little doubt that reduced functioning and other con-sequences of living with pain can lead to feelings of loss andthus adversely affect mood. Yet, there are a number of behav-iors that contribute to functional impairment that may directlyor indirectly contribute to an increased risk for depression.Here, two key behaviors are described: poor sleep hygiene andfear-based avoidance. Beginning with the former, a criticaltriad is formed between sleep, pain and depression [62–64]. Ifany one of the three factors worsen or improve then the othertwo are usually impacted as well. Thus, engaging in any oneof the multitude of behaviors that are not conducive to sleepand experiencing chronic sleep disturbance could possiblyexplain the onset of depression in an individual with chronicpain. A recent study showed that therapies that specificallytarget sleep disturbance can result in an improvement infunctioning [65].

Avoidance and withdrawal are common in both depressiveand pain populations. Fear is often one potent factor that canunderlie decreased activity and social interaction. Accordingto the fear avoidance model of chronic pain, individuals whoperceive pain as threatening, typically respond with pain-related fear avoidance behavior which results in decreasedfunctioning and disability [66, 67]. Such changes in function-ing and social support can lead to poor mood and, potentially,depression. Thus, cognitive behavioral therapy (described inmore detail below) specifically implements a number of

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activation strategies to get individuals moving again and, in asystematic way, move past their irrational fears [68–70].

Evidence Based Treatment for Comorbid Painand Depression

Given the overlapping neurobiological processes and psycho-logical factors described above, it is not surprising that painand depression respond well to similar treatment such aspharmacotherapy, cognitive behavioral therapy, or a combi-nation. Amitriptyline (TCA) [25, 71] and venlafaxine,duloxetine, and milnacipran (SNRIs) [72, 73] are recommend-ed treatment for numerous pain conditions. According to arecent review [25], amitriptyline, duloxetine, and milnacipranare considered first line options for treating fibromyalgia.Several recent meta-analyses on SSRIs [26, 71] have conclud-ed there is limited evidence for their use to treat pain specif-ically, but they are recommended for comorbid symptoms ofdepression. An RCT in patients with chronic pain and comor-bid depression found that the treatment group (12 weeks ofoptimized antidepressant therapy followed by six sessions of apain self-management program) experienced a significant re-duction in both pain severity and depression that weresustained over 12-months [74]. Due to the sequential studydesign and the finding that the strongest effects were alreadyevident following the antidepressant therapy and prior tobeginning the behavioral component of the program, theimpact of the addition of the self-management element isdifficult to interpret. Nonetheless, the results of this studyare important and show that chronic pain patients who aredepressed benefit from antidepressants. One of the shortcom-ings of pharmacotherapy research is there are few head to heador dual medication (combination) therapy trials in patientswith comorbid pain and depression [72]. Additional researchis needed to identify subgroups of patients within differentchronic pain conditions and varying levels of depression thatare likely to benefit from the addition of a TCA or SNRI.

Cognitive behavioral therapy (CBT) has been part of treat-ment for chronic pain for decades and the majority of researchsupports the use of CBT (and variants such as acceptance andcommitment therapy) as an effective intervention for differenttypes of pain conditions [75–78]. Although CBT is rooted inthe psychological treatment of depression, depression is notalways directly addressed in CBT when applied to pain man-agement. Instead, CBT for pain typically focuses on symptomrelief and increasing physical functioning. For instance, pa-tients are taught how to 1) alter unhelpful thoughts and beliefsin a manner that is better aligned with the management of pain,and 2) use new behavioral skills to decrease pain and increasefunctioning [79]. Although the focus of CBT does not neces-sarily address depression per se , alleviation of painful

symptoms or increasing physical activity may subsequentlyimprove mood.

One major obstacle is that dissemination of evidence-basedCBT programs into real world clinic settings is challenging.Lack of access to what works and a lack of trained providersmean that many patients do not receive evidence-based care.Another barrier is that patients in medical settings often do notfollow up on referrals to CBT. A recent study found that CBTis the most frequently declined service by patients in multi-disciplinary care [80]. Therefore, a critical next step is con-sidering ways to make evidence based interventions like CBTmore appealing and widely accessible to patients. One possi-ble solution may be incorporating Internet-based cognitivetherapy (iCBT) when CBT is not available. This form oftherapy incorporates the principles of CBT, but the interven-tions are delivered over the Internet. A recent review of iCBTinterventions for chronic pain concluded that iCBT improvespain outcomes [81]. The Pain Course is an iCBT programspecifically developed for managing chronic pain and emo-tional wellbeing [82•]. The results from the RCT comparingthe Pain Course to standard of care found that participants inthe treatment group reported reduced pain severity and de-pression. So far the data are encouraging and suggest iCBTmay be a good treatment option for some patients. However, itremains unclear how best to incorporate iCBT into clinicalcare.

Conclusion

In this review, we have described the most current researchregarding the association between pain and depression. Thetake home message from decades’ worth of research is clear:pain and depression are intricately connected through sharedneurobiological processes and psychosocial factors. However,despite their high comorbidity, pain and depression representindependent dimensions to pain and there is still much thatremains unknown. For instance, research on the interactionbetween pain and depression in the central nervous system isstill evolving, and advancing our understanding of the simi-larities and differences in the underlying neurological mecha-nisms has important implications for treatment. Recent ad-vances in neuroimaging and experimental pain testing may bekey to helping researchers identify how pharmacological andpsychological (e.g., CBT) interventions alter objective mea-sures of pain perception.

The optimal treatment approach for comorbid pain anddepression should simultaneously address both physical andpsychological symptoms. From a clinical perspective, if apatient has both pain and depression, treating one withouttreating the other is contraindicated and may adversely impactoutcomes. Better screening procedures for depression in painpatients (and patients presenting with somatic complaints) and

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dissemination of evidence-based treatments that address co-morbid symptoms is critical. In another decade’s time, areview of this same literature should demonstrate an improve-ment in the treatment of pain and depression.

Compliance with Ethics Guidelines

Conflict of Interest Jenna Goesling declares that she has no conflict ofinterest.

Daniel J. Clauw has received research support from Pfizer, Cerephex,Eli Lily, Marck, Nuvo, and Forest; served as a consultant for Pfizer,Cerephex, Eli Lily, Marck, Nuvo, Forest, Tonix, Purdue, Theravance,and Johnson & Johnson; and provided expert testimony for Pfizer, EliLilly, and Forest.

Afton L. Hassett has received research support from Bristol-MyersSquibb and Pfizer.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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