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Sleep Medicine Reviews 17 (2013) 173e183

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Sleep Medicine Reviews

journal homepage: www.elsevier .com/locate /smrv

THEORETICAL REVIEW

The comorbidity of insomnia, chronic pain, and depression: Dopamine asa putative mechanism

Patrick H. Finan*, Michael T. Smith a

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Dr., Suite 100, Baltimore, MD 21224, USA

a r t i c l e i n f o

Article history:Received 9 December 2011Received in revised form2 March 2012Accepted 13 March 2012Available online 29 June 2012

Keywords:InsomniaChronic painDepressionDopamineStressAffectOpioids

* Corresponding author. Tel.: þ1 410 550 7901; faxE-mail addresses: pfinan1@jhu.edu (P.H. F

(M.T. Smith).a Tel.: þ1 410 550 7000; fax: þ1 410 550 1117.

1087-0792/$ e see front matter � 2012 Elsevier Ltd.doi:10.1016/j.smrv.2012.03.003

s u m m a r y

Epidemiological, cross-sectional, and prospective studies suggest that insomnia, chronic pain, anddepression frequently co-occur and are mutually interacting conditions. However, the mechanismsunderlying these comorbid disorders have yet to be elucidated. Overlapping mechanisms in the centralnervous system suggest a common neurobiological substrate(s) may underlie the development andinterplay of these disorders. We propose that the mesolimbic dopamine system is an underappreciatedand attractive venue for the examination of neurobiological processes involved in the interactions,development, exacerbation, and maintenance of this symptom complex. In the present article, studiesfrom multiple disciplines are reviewed to highlight the role of altered dopaminergic function in thepromotion of arousal, pain sensitivity, and mood disturbance. We argue that studies aiming to elucidatecommon factors accounting for the comorbidity of insomnia, chronic pain, and depression shouldevaluate functioning within the mesolimbic dopaminergic system and its effect on common processesknown to be dysregulated in all three disorders.

� 2012 Elsevier Ltd. All rights reserved.

Insomnia is a prevalent sleep disorder, with a least 6% of thepopulation meeting stringent diagnostic criteria, and as many as48% presenting with symptoms.1 Psychiatric and medical comor-bidities commonly present with insomnia, necessitating a trans-disciplinary approach to research and treatment conceptualization.Chronic pain is one of the most common comorbidities, and hasbeen linked to insomnia at the population level through epidemi-ological surveys.2 Finer-grained prospective and experimentalinvestigations have convincingly characterized sleep and painsymptoms as reciprocally interacting.3e5 Current research effortshave focused on identifying common pathways through whichneurobiological and psychosocial mechanisms of chronic pain andinsomnia covary to enhance risk for symptom amplification andfunctional decline. Similarly, separate inquiries at multiple levels ofanalysis have implicated depression as a prominent comorbidity ofboth insomnia (for a review, see6) and chronic pain (for a review,see7).

Taken together, epidemiological, cross-sectional, and prospec-tive studies converge on the general notion that insomnia, chronicpain, and depression are mutually interacting, each increasing the

: þ1 410 550 1117.inan), msmith62@jhmi.edu

All rights reserved.

risk for the emergence and/or exacerbation of the other. However,few studies have systematically conceptualized and investigated allthree disorders and their symptoms as a cluster. The relative dearthof studies, together with differences in methodologies across them,has resulted in a lack of clarity regarding which common factorsaccount for the clustering of these disorders. The inconsistenciespresent across studies may be due to the fact that most haveemployed symptom-level measurements, which introduceheterogeneity into the classification of the disease phenotype (e.g.,insomnia). Smith et al.8 reported that 88% of patients with one ofa variety of chronic pain disorders (N ¼ 51) self-reported at leastone insomnia complaint, and that their overall sleep quality indexwas statistically indistinguishable from that of primary insomniacs.Despite these descriptive findings, pain severity did not predictseverity of sleep disturbance, a result that runs counter to tradi-tional conceptualizations of secondary insomnia. Similar findingselsewhere have led researchers to consider insomnia and itstreatment from a multidimensional perspective that integrates theevaluation of sleep quality with temporally adjacent changes inphysical (e.g., pain) and psychological (e.g., cognitive-behavioral)concomitants.8e10

The two most prominent studies to have investigated the pop-ulation prevalence of insomnia in chronic pain disorders haveoffered dramatically different estimates, but methodologicaldifferences make it difficult to resolve the discrepancies. Taylor

Abbreviations

COMT catechol-O-methyltransferase geneCREB cAMP response element bindingDA dopamineDAT DA transporterDAT1 DA transporter geneDHPG dihydroxyphenylglycolDNIC diffuse noxious inhibitory controlDOPA dihydroxyphenylalanineDOPAC dihydroxyphenylacetic acidDRD4 D4 receptor geneFDG fluoro deoxy glucoseNREM non-rapid eye movementPET positron emission tomographyREM rapid eye movementRLS restless legs syndromeSNP single nucleotide polymorphismSPECT single photon emission computerized tomographyVNTR variable number tandem repeat

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et al.11 defined insomnia as the presence in the past month ofproblems either with sleep latency or mid-sleep awakenings andfound population insomnia prevalence estimates of 39.8% infibromyalgia, 27.3% in arthrosis, 25.6% in rheumatoid arthritis, 17.6%in tension-type headache, and 16.8% in migraine, among a sampleconstituted of 29% African Americans in Tennessee. In contrast,Sivertsen et al.12 defined insomnia based on a self-report affirmingthe presence of insomnia for at least six months, described bya combination of sleep onset latency, wake after sleep onset, anddaytime complaints obtained through a daily sleep diary. Usingthese criteria, the authors observed population insomnia preva-lence estimates of 48.6% among white Norwegians with chronicpain, broadly defined. In light of these discrepancies, it is evidentthat population comorbidity estimates between diagnoses arelimited by a lack of standardization in measurement.

To ameliorate problems due to methodological inconsistenciesand improve our understanding of how and when symptomscluster in insomnia, chronic pain, and depression, an approach thataddresses putative mechanisms is needed. As all three conditionsare principally regulated by central nervous system mechanisms, itis intuitive to turn to the brain for answers about which commonpathways explain variance in the observed comorbidities and riskestimates.

Although there is likely a large degree of equifinality, wehypothesize that the mesolimbic dopamine (DA) system is anattractive starting point in the effort to unravel common mecha-nisms, given its direct role in the regulation of the hallmarksymptoms of insomnia, chronic pain, and depression. Weacknowledge the likely role that other neurotransmitter systems,such as serotonin and norepinephrine, play in providing a broadcentral nervous system substrate linking sleep, pain, and mood.Readers are referred to prior reviews linking these systems andsymptom clusters.13e15 Relative to other neurotransmitter systems,the mesolimbic DA system, however, has received less attention inthe literature on insomnia, chronic pain, and depression. To ourknowledge, no study has attempted to explain the influence of themesolimbic DA system on the interrelations of these three disor-ders. The goal of this review, then, is to draw together otherwisedisparate lines of evidence and advance a potentially unifying,though not exhaustive, mechanistic model of the comorbidity ofinsomnia, chronic pain, and depression. A comprehensive phar-macologic review of DA and closely linked neuropetide systems is

outside the scope of this paper, and has been conducted else-where.16,17 Rather, here we provide an overview of the evidence insupport of the common mechanisms through which mesolimbicDA activity may promote the comorbidity of insomnia, chronicpain, and depression. We start by first briefly reviewing evidencefor the clustering of symptoms of the triad of insomnia, chronicpain, and depression. Subsequently, we review the evidence insupport of DA as a common substrate of each disorder and proposea model through which DAergic dysfunction may increase vulner-ability for the development and/or maintenance of thesecomorbidities.

Summary of studies simultaneously investigating insomnia,pain, and depression

Although relatively fewer studies have examined the triad ofinsomnia, chronic pain, and depression e or their symptoms e

together in one model, there is growing support for the hypothesisthat the three disorders are linked through common mechanisms.Wilson et al.18 examined comorbidities in a sample of chronicmusculoskeletal pain patients and found that those diagnosed withdepressionwere significantlymore likely to have insomnia. Further,patients with both comorbidities reported greater affective distressand pain severity than either those with comorbid insomnia aloneor those without comorbid depression or insomnia. The causalordering of these relationships is not clear. A prospective mediationstudy found that negativemoodmediates the relationship betweensleep and pain,19 but a cross-sectional study demonstrated thatsleep quality mediates the relationship between pain and symp-toms of depression.20 Still other studies have pointed to a directrelationship between sleep and pain over and above the effect ofdepression symptoms. For example, Chung and Tso21 found thatthree months of pharmacotherapy for depression did not attenuatethe effects of either self-reported insomnia symptoms or objectivepolysomnography parameters on pain symptoms observed duringan acute depressive episode. A number of other studies have foundthat significant associations between insomnia severity andmusculoskeletal or headache pain remain after controlling fordepression symptoms in chronic pain samples.18,22e24 These latterstudies, however, were limited in that formal mediational analyseswere not conducted.

Two additional prospective studies have sought to establishtemporal and directional parameters for these relations, but theresults are still mixed. Nicassio and Wallston25 reported that painand sleep interact to prospectively predict depression symptoms at2-year follow-up for rheumatoid arthritis patients. Specifically,individuals with higher pain and worse sleep at time 1 had moredepressive symptoms at time 2 than individuals with eitherproblem in isolation.25 A recent study of fibromyalgia patientsevaluated sleep disturbance, pain, depression symptoms, andphysical function at baseline and one-year follow-up.26 Throughpath analysis, the authors demonstrated that baseline sleep pre-dicted follow-up pain, baseline pain predicted follow-up physicalfunction, and baseline physical function predicted follow-updepression symptoms, while no baseline variable predictedfollow-up sleep. This analysis highlights the unique findings thatemerge when the relationships between sleep, pain, and depres-sion are examined prospectively, but is limited in its explanatorypower due to the extensive temporal separation of its two assess-ment points.

To combat this potential confound and evaluate the temporaldynamics of sleep, pain, and depression symptoms, micro-longitudinal designs, incorporating repeated assessments in closeto real-time, have been employed. A recent daily diary study foundthat poor nighttime sleep quality predicted increases in next-day

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pain severity to a greater extent among chronic pain patients withhigher versus lower levels of depression symptoms.19 In anecological momentary assessment study, rheumatoid arthritis andfibromyalgia patients who reported poor sleep quality perceivedgreater negative affect and lower positive affect e both risk factorsfor depression27 e when pain was elevated relative to when painwas closer to the mean.28 Although there were no diagnosticdifferences found in the experience of negative and positive affect,fibromyalgia patients reported greater pain and worse sleep qualitythan rheumatoid arthritis patients.28

Despite these promising results from cross-sectional andprospective studies demonstrating complex interactions betweensleep disturbance, pain, and symptoms of depression, the direc-tionality of effects is mixed, and it is not clear which mechanismsaccount for them. Although more prospective studies measuringall three symptoms complexes are needed to clarify the temporalcomplexities, the evidence suggests that each has the potential tomoderate and/or mediate the expression of the other. The robust,multidirectional linkages between these symptoms observed inextant longitudinal data raises the distinct possibility that theyare regulated by a common neurobiologic substrate or set ofsubstrates. A systematic, multilevel research agenda seeking toidentify these putative substrates for the insomnia, chronic pain,and depression triad has the potential to improve our under-standing, treatment and prevention of these disorders. Below weassemble evidence implicating altered mesolimbic DA processingas a putative mechanism underlying insomnia, chronic pain, anddepression.

The role of DA in sleep disorders

Mesolimbic DA and arousal

DA is a neurotransmitter from the catecholamine family that isconsidered to be a key neurobiological substrate of reward, and hastraditionally been the target of pharmaceutical therapies formovement disorders, psychotic disorders, and to a lesser extentdepression. Evidence also indicates, however, that DA is integral tothe promotion and maintenance of arousal states (for reviews,see29,30).

Mesolimbic DA neurons originate in the ventral tegmental areaand the substantia nigra pars compacta, and project to bothsubcortical and cortical structures relevant to the sleep/wake cycle,including the nucleus accumbens, striatum, prefrontal cortex, andanterior cingulate cortex.31,32 DA receptors are abundant in keystructures of the ascending reticular activating system, includingthe dorsal and median raphe nuclei and the ventral periaqueductalgray, which are critical in modulating sleep.16,33 Depletion of DA inhumans via a competitive inhibitor of a key DA enzymatic precursorprovokes sleepiness, which correlates with prolactin increase andincreased glucose metabolism in the periaqueductal gray and leftinsula.34 Experimentally/pharmacologically-induced arousal states,too, are associated with altered DA neurotransmission.

DA neurotransmission has been proposed as a primary mecha-nism for the arousal-promoting effects of exogenous stimulants(i.e., amphetamine, cocaine, and methylphenidate), which areknown to be related to sleep disturbance and insomnia, during bothacute and abstinence phases.35e37 An elegant series of studies byWisor et al.38 revealed that both methamphetamine and modafinil,an analeptic drug designed to treat narcolepsy and daytimesleepiness, increased extracellular DA by blocking the DA trans-porter (DAT) receptor, which regulates DA reuptake. DAergic toneand wakefulness were increased in narcoleptic dogs followingtreatment with amphetamine and modafinil, while neither drughad awake-promoting effect in DAT-knockout mice, supporting the

notion that the DAT receptor mediates amphetamine andmodafinil-induced wakefulness.38 More recent mouse studies haveimplicated D1 and D2 receptors in the wake-promoting effect ofmodafinil.39,40 PET imaging has confirmed these effects in humans,with differences in radiotracer binding observed in the striatumand nucleus accumbens.41 Thus, exogenously administered stimu-lants appear to promote wakefulness directly through action in themesolimbic DAergic system. Indeed, DAergic agents are oftenutilized to treat daytime sleepiness and disorders associated withfailing to maintain adequate daytime arousal. These basic sciencefindings, however, also provide a general basis for DA neurotrans-mission involvement in sleep abnormalities associated withexcessive central nervous system arousal, with functional alter-ations observed in brain regions associated with the mesolimbicDAergic system.

DA signaling alterations have long been understood to be inte-gral to the pathophysiology of a variety of sleep disorders, andunderstanding the role of DA in these disorders may inform thepursuit of a shared pathophysiological basis of insomnia, chronicpain, and depression. One such disorder is narcolepsy, a sleep/arousal disorder characterized by rapid eye movement (REM) sleepabnormalities and excessive daytime sleepiness. The hypothalamicpeptide orexin (also known as hypocretin), which binds to orexin 1and orexin 2 receptors on ventral tegmental DAergic neurons,42,43

increases nucleus accumbens DA release,43 and is strongly linkedto arousal and the maintenance of wakefulness.44 Convincingevidence suggests orexin is deficient in narcolepsy.45

An additional disorder for which DA abnormalities have beenobserved is restless legs syndrome (RLS), a sleep-related movementdisorder characterized by a chronic urge to move the limbs duringwakefulness with a pronounced circadian pattern in symptomexpression that often interferes with sleep onset. Allen46 reviewedthe evidence for DA in the pathophysiology of RLS and tentativelyconcluded that nigrostriatal DA dysfunction may contribute to RLSsymptoms, while low-dose DA agonists generally reduce symptoms.A more recent study of postmortem RLS brain tissue supportedthose earlier findings by demonstrating reduced D2 receptors in theputamen of RLS patients.47 Clinically, RLS is associated withinsomnia,48 as well as objective markers of sleep dysfunction andarousal, including increased sleep latency, decreased sleep effi-ciency, and excessive sleep instability.49e51 A recent pharmacolog-ical trial revealed superior efficacy of the preferential D3 agonistpramipexole, relative to the preferential D2 agonist bromocriptine,in treating insomnia symptoms in RLS.52 These findings highlightthe often underappreciated feature of arousal in RLS and providea further basis from which to hypothesize that DA abnormalities,mediated by activity at multiple receptor subtypes, may contributeto sleep-interfering states of arousal and, by extension, insomnia.

Genetic findings implicating the potential role of DAneurtransmission in arousal

Genetic studies offer another tool to evaluate the role of DA inarousal-related sleep problems. A well-studied single nucleotidepolymorphism (SNP; val158met) on the catechol-O-methyltransferase gene (COMT) leads to differences in DAmetabolism by effecting alterations to the thermostability of theCOMT enzyme. Individual differences in the val158met genotypehave been associated with differences in alpha wave oscillationsin REM and non-rapid eye movement (NREM) sleep. Specifically,the met/met genotype, which is associated with decreased DAmetabolism, and therefore abnormally elevated levels of tonicDA, is associated with higher peak amplitude of the alpha waveform during wakefulness, and greater 11e13 Hz activity in bothREM and NREM sleep relative to the val/val genotype, which is

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associated with greater DA metabolism.53 Although the samplesize was small (N ¼ 22), and the finding has not yet been repli-cated, to our knowledge, it nonetheless provides preliminaryevidence that genetic differences in a key DA gene known to beimplicated in both chronic pain and depression (reviewed below)are associated with heightened states of arousal during sleep.

Other DA-relevant genes have also been implicated in sleepdisturbance. A variable number tandem repeat (VNTR) poly-morphism on the D4 receptor gene (DRD4) was associated withinsomnia-like symptoms in people with Alzheimer’s disease,54 aswell as smokers following cessation.55 At present, however, theliterature on DA genes and sleep is inconclusive and prone toinconsistencies across studies. For example, a recent study of a VNTRpolymorphism on the DA transporter (DAT1) gene that had previ-ously been associated with cocaine abuse and DAT1 transcriptionaldifferences found that the polymorphism was not associated withvariability in sleep measured through polysomnography.56 Thus,more research is needed to clarify early genetic findings as genomicand phenotypic methods are refined. If genetic variation associatedwith functional alterations in DA neurotransmission does, indeed,contribute to a general arousal-based phenotype, we would expectto observe downstream differences in DA processing among peoplewith clinical sleep disorders relative to good sleepers. Ultimately,translational studies linking genetic variants to clinical sleepdisorders via intermediate phenotypes descriptive of geneticfunction (e.g., transcription factors), objective clinical markers(e.g., polysomnagraphy), and subjective psychosocial variables(e.g., affect regulation) will need to be conducted.

Is DA involved in primary insomnia?

Following the observation that DA is associated with arousalin animal models, human neuroimaging models, genetic models,and sleep-related movement disorders, it is intriguing to ques-tion whether DA may also contribute to arousal-related sleepdysfunction in other sleep disorders with a less well-establishedpathophysiological basis, such as insomnia. Decades of researchon insomnia frame it as a disorder of 24 h hyperarousal.57,58

Although the precise neurobiology of insomnia remains poorlyelucidated, there is growing evidence for a neurobiological basisfor the hallmark hyperarousal symptoms.59,60 DA neurotrans-mission, however, has rarely been targeted as a possible mech-anism for chronic insomnia despite its rather robust associationwith arousal. Some notable exceptions highlight the promise oftargeting DA neurotransmission in insomnia. Vgontzas et al.61

reported positive correlations between polysomnographic indi-cators of sleep disturbance (i.e., sleep latency; wake after sleeponset) and urinary levels of the DA precursor dihydrox-yphenylalanine (DOPA) and the DA metabolites dihydrox-yphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG)in individuals with primary insomnia. In regression analyses, theDA-related variables were stronger predictors of sleep distur-bance indices than plasma cortisol. The authors interpreted theresults as evidence that sleep-related arousal in chronic insomniaactivates a sympathetic stress response mediated by catechol-amines. More recently, pilot neuroimaging studies of primaryinsomnia provide indirect, exploratory support for the possibilityof a DA-insomnia link. Prior work by our group measuredregional cerebral blood flow via single photon emissioncomputerized tomography (SPECT) imaging during NREM sleepshortly after the emergence of the first sleep spindling or Kcomplex.62 This study found the basal ganglia, a major DAergicstructure implicated in movement disorders, to demonstrate themost robust perfusion abnormality relative to good sleepercontrols. Other work using fluoro deoxy glucose (FDG) positron

emission tomography (PET) imaging to compare differencesbetween the pre-sleep state and NREM sleep in primaryinsomnia and controls found several brain regions to be hyper-metabolic in primary insomnia during NREM.63 Consistent withthe hyperarousal hypothesis of insomnia, these authors foundprimary insomniacs to demonstrate greater activations in theascending reticular activating system, mesial temporal cortex,thalamus, hypothalamus, cingulate gyrus, and insula.

There is clearly a need to conduct studies that directly investi-gate the role of DA as a putative pathophysiological mechanism ininsomnia. Some of the above referenced studies directly implicatingDA-related genetic variation in insomnia symptoms related toAlzheimer’s disease54 and nicotine withdrawal,55 raise the possi-bility that DA might play a role in insomnia disorders more gener-ally, including primary insomnia. Interestingly, several experimentshave found that sleep deprivation increases endogenous DA tone, asevidenced by reduced [11C]raclopride binding to D2/D3 receptors inthe striatum and thalamus of healthy human subjects.64,65 A recentstudy inmice similarly showed increases in endogenous DA bindingto D3 receptors following sleep deprivation.66 These findings areparticularly intriguing to consider with respect to a potential role ofDA in the maintenance of chronic insomnia. Although hyper-vigilence is not typically associated with acute sleep deprivation inhealthy subjects, thismaynot be the case for patientswith insomniawho often exhibit mild, chronic partial sleep deprivation. Acutesleep deprivation in healthy subjects is most commonly associatedwith excessive daytime sleepiness, presumably because sleep-related homeostatic processes override wake-promoting arousalmechanisms that might be influenced by enhanced DAergic tone.Indeed, Volkow et al.64,65 interpreted their findings to indicate thatenhanced endogenous DA tone during sleep deprivation may haveresulted as a compensatory opponent process combating theprimary drive to sleep, and suggested that the suprachiasmaticnucleus, with direct innervations of the striatum and mesenceph-alon, may regulate this homeostatic process. With respect tochronic primary insomnia, Stepanski and colleagues67 demon-strated that patients exhibit a diminished homeostatic response tosleep deprivation. This finding suggests the possibility that patientswith insomniamay bemore vulnerable to sleep-interfering states ofarousal occurring in the context of mild chronic sleep deprivation.

As we have discussed, insomnia is rarely a disorder that occursin isolation, and often presents comorbid with chronic pain and/ordepression. Understanding a more clearly defined role of DAdysfunction in those disorders may shed light on how similarabnormalities may precipitate or result from insomnia, and mayhelp clarify the well-recognized but poorly elucidated comorbidityof insomnia, chronic pain, and depression. Indeed, many of themesolimbic DAergic system structures found to be activated ininsomnia and other conditions of disturbed sleep have also beenassociated with pain processing and mood, suggesting that DA mayimpact both the development and descending control of commonsymptoms of chronic pain, and depression. We turn here to theevidence supporting DA’s role in chronic pain.

The role of DA in chronic pain

The notion that DA is involved in pain regulation follows fromthe observation that endogenous DA in the mesolimbic DA systemmay produce analgesia. Specifically, lesions to the ventraltegmental area lead to increased sensitivity to pain, while stimu-lation to the same area produces analgesia.68 The process by whichDA is thought to promote chronic pain states, however, is complexand first requires an understanding of the homeostatic checks andbalances of DA neurotransmission in steady state. Under normalconditions, tonic DA is released into the extracellular fluid in

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a phase-independent fashion by glutamate, and builds to a steadystate level. Phasic DA, in contrast, is characterized by rapid burst-firing of activated DA neurons, and is released in quantities suffi-cient to saturate the D2 receptors in the synaptic cleft in response toelevations in pain.69 To maintain homeostatic DA levels at steadystate, increases in tonic DA concentrations result in compensatoryinhibition of phasic DAergic firing by modulating presynaptic glu-tamatergic inputs.69 Presynaptic activation of prefrontal cortical D2receptors by tonic DA has been shown to inhibit DA neuron firing inthe nucleus accumbens, whereas presynaptic activation of hippo-campal (ventral subiculum) D1 receptors by phasic DA has theopposite effect.70 The opposing processes of presynaptic D1 and D2receptor regulation of afferent DA neuronal inputs in the nucleusaccumbens requires a delicate balance of tonic and phasic DA firingto maintain homeostasis. An excess of tonic versus phasic DA, then,would be expected to inhibit mesolimbic DA neuronal activity.Clinically, an excess of tonic DA may be maladaptive for individualswith chronic pain in that it should both promote arousal and inhibitDA analgesia in response to pain flares. Through this lens, wespeculate that the high comorbidity between chronic pain andinsomnia may be partially accounted for by a fundamentaldysfunction in tonic versus phasic DAergic neurotransmission.

Patients with facial pain, as well as those with fibromyalgia, anidiopathic widespread musculoskeletal pain disorder thought to bemaintained primarily by central nervous system abnormalities,71,72

have reduced DA metabolite concentrations in the cerebrospinalfluid.73e75 On the surface, these findings would appear to contra-dict the hypothesis that DA abnormalities underlie the comorbidityof insomnia and chronic pain in light of the wealth of data pointingto abnormally elevated levels of DA in states of arousal. However,the seemingly paradoxical findings can be clarified through ourunderstanding of the homeostatic regulation of tonic versus phasicpain. If the phasic DA response to pain is chronically inhibited byelevated tonic levels, then we would expect less DA metabolite inthe cerebral spinal fluid, which should primarily consist of post-synaptic phasic DA cleared from the synapse through reuptake.Providing further support for the tonic/phasic hypothesis, onestudy showed that in response to injection of hypertonic saline,fibromyalgia patients experience more pain and release less phasicDA than control subjects.76 Moreover, healthy controls release DA inthe striatum in response to sustained pain, whereas fibromyalgiapatients do not.76,77

COMT, which directly regulates tonic, but not phasic DAmetabolism, has been proposed as a pain-modulating gene, andallelic differences have been reported in fibromyalgia,78e80 osteo-arthritis,81 migraine,82 and tension-type headache,83 such that thelow DA metabolism genotype (met/met) tends to be more frequentin cases than controls. Further, three COMT haplotypes have beenassociated with high, low, and average pain sensitivity. Possessionof the average or high pain sensitivity haplotypes increases theodds of developing temporomandibular joint disorder by 2.5times.84 Recent gene X environment studies indicate the effect ofCOMT on pain may be moderated by cognitiveeaffective processesthat are relevant to DAergic processing. Carriers of a low activityCOMT diplotype who tended to catastrophize about their pain re-ported greater pain following knee replacement surgery thancarriers of the high activity diplotype and non-catastrophizingcarriers of the low activity diplotype.85 In a separate within-person microlongitudinal study, fibromyalgia patients who werehomozygous for the low activity met158 allele on the val158met SNPreported greater pain on days in which their catastrophizing waselevated than patients homozygous for the high activity val158

allele.86 Some evidence indicates that the changes to DA metabo-lism conferred by COMTmay be limited to tonic DA in the prefrontalcortex,87 which is in line with the genotype-specific effects

observed for pain-modulating effects of catastrophizing, a negativeaffectively laden cognition that may be regulated by prefrontalcortical circuits.88,89 To the extent that dysfunction in prefrontalcortical DA neurotransmission affects striatal, cingulate, and insularDA burst-firing,89e92 chronic pain may be perpetuated amongindividuals with poor tonic DA regulation.76

The role of DA in depression

Although serotonin and norepinephrine signaling in the hippo-campus and frontal cortex has been the target of a large proportion ofthe research on depression and its treatment, a growing body ofresearch has turned the attention toward DA neurotransmission inthe mesolimbic DA system.93e95 Meta-analysis has confirmed thatdepression is a significant comorbidity of cocaine addiction, which isassociatedwithmesolimbic DA abnormalities.96 The dysregulation ofemotions characteristic of depression involves not only an increase innegative emotions, such as hopelessness or anger, but also a relativedepletion of positive affective resources, such as the ability toexperience reward. A hallmark of depression is a breakdown of themotivational drive to cope with life’s challenges, leading to behav-ioral withdrawal and inhibition.97,98 Mesolimbic DA-mediatedanhedonia, or the inability to experience reward from natural rein-forcers, may underlie this motivational-affective disturbance.99

Although neuroimaging studies have yielded equivocal resultswith regard to DA binding differences in depressed patients relativeto controls,94 psychological stress, a general but fundamentalsymptom of depression, has been convincingly linked with DA.Stress has been shown to acutely activate DA neurons in the ventraltegmental area and promotes increases in tonic DA in the nucleusaccumbens.100,101 In the short term, stress-induced DAergicneurotransmission may be adaptive, in as much as activationwithin the nucleus accumbens may drive motivation to cope withstress and enhance the experience of natural reward in the event ofcoping success and/or stress relief.102 Affect, however, is especiallydysregulated during periods of chronic stress,103 suggesting thatsustained mesolimbic DA activation is maladaptive.104 Studies ofchronic cocaine use support these findings. For example, byrepeatedly potentiating phasic DA release, chronic cocaine use isassociatedwith reduced D2 receptor availability in the striatum andnucleus accumbens of detoxified cocaine addicts.105 Over time, D2receptor function may change as a result of chronic phasic activa-tion, thereby creating a state in which natural rewards lose theirability to stimulate phasic DA activity at the D2 receptor106,107 andaffect becomes dysregulated.108 Diminished mesolimbic phasic DAfunction, a process also engendered by inhibitory tonic DA activity,may contribute to the elevated risk for depression to developduring and/or subsequent to active substance abuse.109

Early major life events, too, may prime the mesolimbic DAergicsystem for later life dysregulation.110 For example, in animalmodels, stress associated with maternal deprivation leads toincreased tonic DA in the nucleus accumbens and amygdala duringadulthood,111 as well as an increased sensitivity to cocaine.112 Inhumans, exposure to negative early life events is a major risk factorfor substance use disorders113 and depression.114 These findings areunderscored by the recent findings that early childhood traumapredicts disordered sleep115,116 and chronic pain117 in adulthood.Relating these findings to DA neurotransmission in humans, it hasbeen shown that in response to an experimental psychosocialstressor, adults who reported poor maternal care evidenced greaterDA release in the ventral striatum than those who reported healthymaternal rearing.118

One mechanism through which stress-induced mesolimbic DAactivation can be appreciated is the transcription of cAMPresponse element binding (CREB) protein (for a review, see119:).

P.H. Finan, M.T. Smith / Sleep Medicine Reviews 17 (2013) 173e183178

Stress stimulates CREB in the nucleus accumbens,120 where itsactivity is mediated by DA through both D1121 and D2122 receptors.Overexpression of CREB has been found to diminish the rewardingvalue of cocaine,123 suggesting a role in promoting anhedonia.Interestingly, behavioral responses to aversive stimuli are alsomuted when CREB is elevated,120 and depressive behavior hasbeen observed during a forced-swim test in animal models.124

Taken together, the evidence suggests that CREB elevationscontribute to emotional dysregulation and may be considereda putative risk factor for depression. As DA neurons may bechronically activated in response to chronic stress, the CREBfindings provide further support for the notion that altered mes-olimbic DAergic neurotransmission contributes to the develop-ment and maintenance of depression.

Summary and future directions

The evidence implicates DA as a neurobiological factor associ-ated with symptoms of insomnia, chronic pain, and depression.However, the exact nature of these associations has yet to beelucidated, and the putative role for DA in insomnia rests primarilyon documented associations of DA with arousal and other arousal-related disorders, and therefore requires rigorous empirical evalu-ation in insomnia itself. It is likely that the DAergic influence on thecomorbidity triad is dependent on receptor subtype, receptorpharmacokinetics, homeostatic regulation of DA release, functionalconnectivity between brain regions, activity of functionally relatedneurotransmitters, metabolic and catabolic factors, genetic differ-ences, environmental differences, and stimulus type, intensity, andduration. Further, although the majority of studies reviewed abovepoint to elevated tonic DA levels as a potential risk factor in themanifestation of sleep, pain, andmood problems, other studies havefound reduced DA concentrations in clinical populations.73,74,125 Assuch, this review runs the risk of oversimplifying the function ofDA as a substrate linking the symptom triad. For example, DA hasbeen proposed as a key substrate in chronic migraine given theabundance of D2 receptors found in the trigeminovascular system,and the increased aura presentation resulting from administrationof D2 agonists (for a review, see126). Despite these findings, DAhypersensitivity in migraine has not been consistently linked tomigraine-related pain, suggesting that the role for DA in chronicpainmay be nuanced and vary as a function of clinical presentation.

Nonetheless, it is reasonable to glean from the evidence pre-sented in this review that a common DAergic abnormality or setof abnormalities may underlie insomnia, chronic pain, anddepression. As reflected in Fig. 1, we propose that DA abnor-malities may perpetuate the experience of insomnia, chronicpain, and depression, and that persistent exacerbations of thesymptoms of these disorders may feed back to promote furtherDA dysregulation, as represented by the bidirectional arrows. Thecurrent literature does not provide guidance regarding thetemporal dynamics of DA’s relationship with these symptoms, soour model refrains from making causal predictions. Therefore, weare limited to making the more general prediction that tonicDAergic functioning will be dysregulated among individuals whohave comorbid insomnia, chronic pain, and depression. A criticalpath to test with this model is the extent to which psychologicalstress moderates the relations of DA and the comorbidity triad.Stress has been shown to have a bidirectional relation withinsomnia,61,127 chronic pain,128,129 and depression,130 wherebystress can both contribute to symptom exacerbation and begenerated in response to symptoms themselves. As describedabove, stress is thought to result in increased tonic DA release,providing a rationale for including stress as a moderator of thepaths from DA dysfunction to illness in Fig. 1.

Another intriguing future research direction is to prospectivelyassess DAergic function among patients with recently acquiredchronic pain. As many of these patients will subsequently developinsomnia and/or depression, the evaluation of DAergic functionbefore and after the development of comorbidities would provideinformation regarding the potential presence or absence ofa comorbidity “dose” effect, whereby DAergic function would beincreasingly compromised as sleep and mood become increasinglydisturbed. Additionally, it would be important to know whetherdysfunctional DA processing can be reversed with symptom reduc-tion following treatment. By studying the separate and combinedeffects of DA neurotransmission on insomnia, chronic pain, anddepression, we can test whether, in the presence of DAergicdysfunction, improvement in one domain (e.g., sleep efficiency) issufficient to bring about changes in DA function, or whether alteredDA processing persists until symptoms in all domains are remitted.Alternatively, the effects of selective DA receptor agonists on thesymptom cluster may be informative. Several of the atypical anti-psychotic medications, which demonstrate strong D2 receptorantagonism have demonstrated efficacy for depression131 andseveral preliminary studies suggest low doses of these medicationsmay be promising in treating refractory insomnia e.g.,132,133. Unfor-tunately, most of these medications such as quietapine have broadereffects on serotonergic, adrenergic and histaminergic receptors,making it difficult to conclude that improvement in sleep ordepression results from specific DAergic mechanisms.

Given the complexity of the mesolimbic DAergic system, it islikely that other interacting neurotransmitter systems maycontribute to, and perhaps augment, the experience of thesecomorbidities. Although discussing in depth the interactive role ofother potential neurotransmitter systems is beyond the scope ofthis review, we highlight the endogenous opioid system asa particularly attractive and relatively novel target given its espe-cially strong linkages to the mesolimbic DAergic systems (fora review, see134). Endogenous opioids have been shown to func-tionally interact with DA,135e139 and are directly implicated in painprocessing140 and depression symptoms141 in regions with heavyDAergic innervation. Further, recent data suggests opioids arerelated to arousal, providing additional motivation to consider theopioid-DA interaction in the comorbidity triad. For example,a handful of studies indicate that sleep deprivation dysregulatesendogenous opioid systems and diminishes the analgesic efficacyof m-opioid receptor agonists.142,143 Animal studies have found thatsleep deprivation alters m- and d-opioid receptor function in mes-olimbic DA circuits,144 diminishes basal endogenous opioid levels inthe brain145 and down regulates central opioid receptors.146 Bothopioids and DA are elevated in the limbic system in response tosleep deprivation, an effect that can be reversed with administra-tion of selective m- and d-opioid and DA D1 receptor antago-nists.147,148 Work by our group in human subjects149 found thatexperimental sleep disruption impairs pain inhibitory capacity inhealthy females using a diffuse noxious inhibitory control (DNIC)test, a procedure that has been shown in prior studies to bemediated by endogenous opioid peptides.150 Thus, as futureresearch efforts target DAergic functioning in the context of thecomorbidity of insomnia, chronic pain, and depression, designs thattest the complementary and interacting influence of opioids will beessential. An excellent example of such a design is the influentialPET neuroimaging study by Zubieta and colleagues,139 whichshowed that healthy COMT met158 carriers (i.e., higher tonic DA)have greater pain, reduced m-opioid system activation, andincreased m-opioid receptor concentrations in the nucleus accum-bens and other limbic regions in response to a sustained painchallenge, suggesting that genetic alterations in DA processingaffect the efficacy of the opioid system in producing endogenous

Fig. 1. Vulnerability model of tonic/phasic DA dysregulation. Solid arrows represent putative bidirectional pathways through which abnormalities in the homeostatic regulation oftonic and phasic DA contribute to the comorbid triad of insomnia, chronic pain, and depression. Dashed arrows represent putative moderators of DA function in this model.

P.H. Finan, M.T. Smith / Sleep Medicine Reviews 17 (2013) 173e183 179

analgesia. These same investigators have demonstrated a role forthe endogenous opioid system during experimental manipulationsof sadness.141 A next step will be to extend such a design to accountfor differences in affect regulation and objective sleep parameters.

A final research direction we will mention here is the exami-nation of positive affect-DA relations in the context of insomnia,chronic pain, and depression. As we have discussed above, DA isdirectly implicated in the processing of natural reward, anddisruptions in DA regulation of reward perception promote affec-tive instability and poor pain outcomes. It remains to be seen ifthese findings help explain variance in the triad of insomnia,chronic pain, and depression, but preliminary research withfibromyalgia patients, who tend to have elevated rates of all threesymptom clusters, suggests this may be a promising direction.Fibromyalgia patients evidence a global deficit in positive affect, aswell as a diminished ability to sustain positive affect during painflares, relative to other chronic pain populations.151,152 A recentcandidate gene study revealed COMT genotype-driven differencesin the dynamics of positive affect and pain among fibromyalgiapatients.153 Specifically, patients homozygous for the met158 allelehad greater difficulty sustaining positive affect during daily

elevations in pain compared to those homozygous for the highCOMT activity val158 allele (i.e., lower tonic DA). Further, fibro-myalgia patients who carried the asp40 allele of the asn40asp poly-morphism on the m-opioid receptor gene (OPRM1), which results ina 7e10 fold reduction in m-opioid receptor protein in culturedcells,154,155 reported higher positive affect compared to those withthe genotype conferring higher levels of m-opioid receptorprotein.153 Thus, the relative balance of DA and m-opioid receptoractivity may be an important component of the etiology of bothpain processing and affect regulation in fibromyalgia. As thispatient population commonly experiences dysregulatedsleep,156e158 it is reasonable to predict that DA and opioid-drivenpositive affective decrements may explain the manifestation ofinsomnia and depression together with ongoing dysregulation ofpain processing. This possibility is underscored by recent researchhighlighting the positive emotional benefits of restorative sleep.159

As more data continue to be gathered in support of the obser-vation that insomnia, chronic pain, and depression are highlycomorbid disorders, the search for common mechanisms willintensify. The mesolimbic DA system has been implicated sepa-rately in each disorder, and is related to processes, such as arousal,

P.H. Finan, M.T. Smith / Sleep Medicine Reviews 17 (2013) 173e183180

that are present in all three disorders. Thus, there is evidence tosuggest that a dysfunction in mesolimbic DAergic functioning mayunderlie the comorbidity of insomnia, chronic pain, and depression.As research methods are refined and more mechanistic data arereported, there may be hope that pharmacological and psychoso-cial treatments will more efficiently and effectively alleviate thesymptoms of this comorbidity triad.

Practice points

1. Patients being treated for primary insomnia, chronic

pain, or depression should be thoroughly evaluated for

the presence of other disorders in the triad. The symp-

toms of each disorder appear to be functionally related,

although no single pathway has been definitively

established, and individual differences in the time

course and expression of symptoms are likely. Clini-

cians should consider the possibility that specifically

targeting each symptommay have beneficial effects on

the other members of the triad. Some evidence for this

is already beginning to emerge, e.g.,(160,161).

2. Patients with centrally-mediated chronic pain, such as

fibromyalgia, may be more likely to experience

comorbid insomnia and depression. Therefore,

preventative counseling to address behavioral issues

pertinent to these disorders, such as sleep hygiene,

may prove beneficial. Such preventative approaches,

however, are only beginning to be tested.

3. Evaluation of the presence of life stressors and the

individual’s coping skills may provide insight into the

onset and/or maintenance of insomnia, chronic pain,

and depression.

4. Evaluation of substance abuse may aid in treatment

conceptualization and planning. Current and/or past

stimulant abusers may be especially vulnerable to the

development of comorbid insomnia, chronic pain, and

depression because their dopaminergic circuits may be

altered as a consequence of repeated activation asso-

ciated with drug intake.

Research agenda

Future research efforts should evaluate

1. The role of the mesolimbic dopaminergic system in

the development and maintenance of insomnia,

chronic pain, and depression with prospective

studies that incorporate current methods of assess-

ment of dopaminergic function, including neuro-

imaging and genetics.

2. the role of psychological stress as a mediator in

models seeking to establish unidirectional or bidi-

rectional paths between dopamine and comorbidity

of insomnia, chronic pain, and depression.

3. The complementary and interacting influence of

opioids on dopaminergic processes in the comor-

bidity of insomnia, chronic pain, and depression.

4. Whether people with comorbid insomnia, chronic

pain, and depression are especially vulnerable to

deficits in positive affect, whether those positive

affective deficits influence and interact with symp-

toms of each disorder, and whether those dysfunc-

tional positive affective processes are attributable to

altered mesolimbic dopaminergic functioning.

Conflicts of interest

None declared.

Acknowledgments

The authors would like to acknowledge funding support fromNINDS/NINR grant T32 NS070201 (PHF) and R01 AR05487, R01AR059410, R01 DE019731(MTS).

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