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The Coexistence of Neuropathic Pain,Sleep,and Psychiatric DisordersA Novel Treatment ApproachCharles E.Argoff,MD*wAbstract:The diagnosis and treatment of neuropathic pain maybe complicated by comorbid conditions such as sleep distur-bances,depression,and anxiety.The interrelationship betweenthe index neuropathic pain state and these comorbidities iscomplex:comorbid conditions exacerbate pain,and in turn,pain exacerbates the comorbid conditions.Because comorbid-itiescannegativelyimpactresponsetopaintreatment,healthcare providers should assess comorbidities as part of thediagnostic work-up,and management strategies should bedesignedtotreatthewholepatient,notjustthepain.Theoretically,therapies that not only reduce pain,but alsoimprove sleep and reduce anxiety and depression can providemultiple benefits without the risk of increased side effectsinherent in combination therapy.Anticonvulsants and anti-depressants have demonstrated efficacy in improving neuro-pathic pain and positively impacting comorbid sleep and mooddisturbances.Novel anticonvulsants that can address one ormore comorbidities in addition to pain may represent viabletreatment options for patients with neuropathic pain.Key Words:neuropathic pain,sleep disturbance,antidepres-sants,anticonvulsants,mood disorders,comorbidities(Clin J Pain 2007;23:1522)Neuropathic pain is a type of chronic pain that isassociated with a primary lesion or dysfunctionwithin the peripheral or central nervous system.1It isestimated that in the United States,approximately 3.75million individuals suffer from neuropathic pain resultingfrom diverse conditions eg,diabetic polyneuropathy(DPN),postherpetic neuralgia(PHN),complex regionalpain syndrome,as well as pain associated with cancer,spinal cord injury,low back pain,and HIV.2Manyinvestigators have now recognized that other chronic painstates,including migraine headache,3and fibromyalgia,4may also have neuropathic features.Given that migraineaffects over 20 million individuals in the United States5and that fibromyalgia may affect approximately 2%ofthe US population,6the prevalence of neuropathic painmay actually be much greater than estimated.As in other types of chronic pain,individuals withneuropathic pain commonly have comorbidities,includ-ing sleep disturbances and mood disorders(ie,depressionor anxiety),which can compound treatment challenges ofthe index disease state and reduce the likelihood of asuccessful clinical outcome.7Because of the similarities inpathophysiology that underlie neuropathic pain,variousneuropathic pain syndromes respond to treatment withneuroactive agentsthat is,antidepressants and antic-onvulsantsthat may also ameliorate some comorbidsymptoms.Therefore,this review will focus on thecomplex interrelationship between neuropathic pain andsleepandpsychiatricdisorders(ie,depressionandanxiety)and the role of antidepressants and antic-onvulsants,especiallynovelanticonvulsants,inthemanagement of patients with neuropathic pain.INTERRELATIONSHIP BETWEEN NEUROPATHICPAIN,SLEEP DISTURBANCE,DEPRESSION,ANXIETY DISORDERS,AND QUALITY OF LIFEMore than 70%of patients with chronic pain reportinterference with sleep,8,9and the majority of thesepatients cite pain as the sole reason for their sleepdisturbance.8Patients with chronic pain also suffer fromdepression and anxiety.10Comorbid sleep disturbance,depression,and anxiety disorders in patients with chronicpain have a profound effect on quality of life.Meyer-Rosberg et al11,12assessed health-related quality of lifeand the burden of illness in 126 patients suffering fromperipheral neuropathic pain using the Short Form 36Health Survey and the Nottingham Health Profile.Patients showed impairment in all aspects of health-related quality of life,both physical and psychologic.Most pronounced were sleep disturbance(reported by88%of patients),lack of energy(86%),difficulty inconcentration(76%),and drowsiness(71%).Patientssuffered emotionally from an inability to work,engage inoutdoor activities,and interact socially.12Because co-morbid conditions can confound the diagnosis of neuro-pathic pain and may negatively impact treatment,acomprehensive evaluation of patients with neuropathicCopyrightr2006 by Lippincott Williams&WilkinsReceived for publication March 19,2005;accepted July 25,2006.From the*Cohn Pain Management Center,North Shore-LIJ HealthSystem,Bethpage;and wNew York University School of Medicine,New York,NY.Reprints:Charles E.Argoff,MD,1554 Northern Boulevard,4th Floor,Manhasset,NY 11030(e-mail:).ORIGINALARTICLEClin J Pain?Volume 23,Number 1,January 200715pain should include an assessment of the impact of painon the patients life.The Brief Pain Inventory13and theMultidimensional Pain Inventory14are pain assessmentinstruments that are widely used in clinical and researchsettings.These self-assessment instruments allow patientsto describe the intensity of their pain and the degree towhich it interferes with sleep,mood,and relationships.NEUROPATHIC PAIN AND COMORBIDSLEEP DISTURBANCEAn Overview of the Nature of SleepPolysomnographic(PSG)studies employing simul-taneous and continuous recording of electroencephalo-gram(EEG),electrooculogram,and electromyogramdemonstrate that sleep is an active process with a uniquearchitecture.15There are 2 distinct states of sleeprapideye movement(REM)and nonrapid eye movement(NREM)(Table 1).The average healthy adult passesthrough 4 stages of NREM sleep,moving from light sleepin stages 1 and 2 to a deep restorative slow-wave sleep(SWS)in stages 3 and 4.After the initial NREM portionof sleep,the first REM period(dream state)occurs,during which a transient increase in body movement anda shift in the EEG pattern from the deep sleep of stage 4to the drowsy sleep of stage 2 occurs.This cycle ofNREM-REM lasts between 90 and 120 minutes and isrepeated 3 to 6 times per night,depending on the durationof sleep.15Reduction of sleep time(normally averaging8h)and continuity has a clear impact on many aspects ofdaytime function,quality of life,and mood.10,1618Comorbid Sleep DisordersThemostcommoncomorbidsleepdisorders,insomnia and excessive daytime somnolence,may beassociated with numerous neurologic diseases,includingchronic pain and depression,general medical diseases,and pharmacotherapy.19Sleep disruption is a commonresult of pain9,20,21;patients with pain commonly showincreased sleep latency,increased wakefulness after sleeponset,increased arousal,and reduced SWS.19Assessment and Diagnosis of ComorbidSleep DisturbanceWhen evaluating a patient with neuropathic painand a sleep disorder,the primary neuropathic paindisorder should be identified first,followed by anassessment of the sleep disturbance.A detailed historyof sleep complaints,including a complete sleep history aswell as medical,neurologic,and psychiatric histories isessential.Any sleep-related breathing disorders shouldalso be noted.Sleep HistoryThe 24-hour sleep history enables both the clinicianand the patient to more clearly identify and quantify theoccurrence of sleep disturbances and any patterns thatmay exist.The sleep history should include a patientinterview and an interview with the bed partner orcaregiver.Questions should probe for signs of excessivedaytime sleepiness,the presence of sleep disorders such asrestless leg syndrome,and factors in the patients lifestyle(eg,diet,caffeine intake,smoking,shift work)that mayimpact sleep.22,23Several instruments have been designedto assess the amount and quality of sleep the patient isexperiencing.The Pittsburgh Sleep Quality Index(PSQI)is a self-rated questionnaire that assesses sleep quality andsleep problems over the previous month.The PSQI hasdemonstrated validity and test-retest reliability in differ-entiating good and poor sleepers among a study popula-tion of normal controls,depressed patients,and patientsdiagnosed with sleep disorders.24Furthermore,in a studyinvolving 80 patients with primary insomnia and 45healthy participants,the PSQI demonstrated high test-retest reliability and a high correlation with sleep logdata.25Among other commonly used sleep scales,theEpworth Sleepiness Scale(ESS)and the Sleep DisordersTABLE 1.Distinguishing Features of NREM and REM SleepNREMREMStage 1(drowsy,light sleep)Stage 5(dream state)Stage 2(light sleep)Stages 3 and 4(deep slow-wave sleep also known as delta wave;restorative)Synchronized EEG;EEG shows slow-wave patterns(ie,low frequencyand high amplitude)Desynchronized EEG;EEG patterns of mixed frequency and lowamplitudeEOG tracings of slow or absent eye movementsEOG tracings displaying bursts of rapid eye movementsEMG recordings reflecting relaxed muscles,with some motor eventsand body repositioningEMG recordings showing paralysis of most major voluntary musclesvia postsynaptic inhibition of spinal motor neuronsSimple cognitionDreamsRegular respiration and heart rateIrregular respiration and heart rateLower body temperature maintained,compared with temperatureduring wakefulnessNo regulation of body temperature*Increased parasympathetic activity and relatively unchangedsympathetic activity,compared with activity in the ANS duringrelaxed wakefulnessIncreased parasympathetic activity and fluctuations in sympatheticactivity,compared with activity in the ANS during relaxedwakefulness*Ultimately,no significant changes in body temperature occur because,in less than 30min,REM sleep cycles into NREM sleep and thermoregulation resumes.ANS indicates autonomic nervous system;EMG,electromyogram;EOG,electrooculogram.ArgoffClin J Pain?Volume 23,Number 1,January 200716r2006 Lippincott Williams&WilkinsQuestionnaire have demonstrated validity in distinguish-ing normal controls from patients with sleep disorders.Ina study involving 30 normal controls and 150 patientsdiagnosed with various sleep disorders,the ESS was ableto identify those patients with sleep disorders andcategorize them according to diagnosis(eg,sleep apnea,narcolepsy).ESS scores correlated with sleep latencymeasured during the multiple sleep latency test andovernight PSG.26The validity and test-retest reliability ofthe Sleep Disorders Questionnaire were also confirmed inseveral studies involving normal controls and patientswith sleep disorders established by PSG.27Sleep diariesthat incorporate both evening assessments regardingdaytimedrowsinessandnapsaswellasmorningevaluations regarding time to fall asleep and number ofawakenings are often useful to evaluate sleep dysfunction(an article by the National Center on Sleep DisordersResearch Working Group22contains an example of asleep diary).Laboratory EvaluationIf a diagnosis cannot be reached using the abovemethods,or if treatment does not improve sleep,a morespecific assessment of the patients sleep dysfunction maybe necessary to determine the presence of sleep apnea,periodic limb movements,or narcolepsy.28PSG,whichsimultaneously monitors EEG,electromyogram(of thesubmentalis muscles and lower extremities),electrooculo-gram(eye movements),and electrocardiogram,as well asrespiratory function,and the Multiple Sleep Latency Test,which measures average sleep latency,the presence ofREM sleep,and REM latency(ie,time to first REMsleep),provide an objective assessment of sleep durationand quality.19Treatment of Neuropathic Pain andComorbid Sleep DisordersNonpharmacologic therapy,including cognitive-behavioral and relaxation techniques,have been effectivein relieving chronic pain and in improving sleep inpatients with insomnia.29Although clear cut benefits ofcognitive-behavioral therapy in patients with neuropathicpain and insomnia have not been demonstrated in well-designed,randomized,controlled trials,the literaturesuggests that some techniques designed to improveinsomnia or pain may reduce pain severity or improvesleep quality in patients suffering from both conditions.30Patients with sleep disorders and chronic painshould be educated about good sleep habits to counteractthe unhealthy sleep patterns they may develop in anattempt to handle their unremitting pain.Behaviors suchas napping during the day and spending a dispropor-tionate amount of time in bed during the day lead to apattern of irregular sleep-wake cycles and fragmentedrather than consolidated nighttime sleep.31Stimuluscontrol and sleep restriction are particularly importantfor these patients and they should be advised to go to bedonly when sleepy,to get out of bed if unable to sleepwithin 20 minutes,and to use the bed only for sleep andsex.The goal is to achieve a sleep efficiency of Z80%;that is,the patient is asleep Z80%of the time he or shespends in bed.31Sleep disturbance in patients with neuropathic painmay also be improved through the treatment of the indexdisease state.Ideal agents are those that have been proveneffective in both neuropathic pain and sleep restoration inrandomized,controlled trials.Treatmentofneuropathicpainoftenincludestricyclic antidepressants(TCAs)and anticonvulsants.TCAs including amitriptyline,desipramine,imipramine,nortriptyline,and clomipramine have been used for manyyears to treat patients with neuropathic pain.32Whenprescribing a TCA for a neuropathic pain patient withcomorbid sleep disturbance,the sedative ability of specificTCAs should be considered in addition to antinociceptiveactivity.For example,desipramine has been shown toalleviate pain in DPN patients,33but it is known todisrupt sleep continuity34and therefore should be avoidedin neuropathic pain patients with a comorbid sleepdisorder.Selective serotonin reuptake inhibitors(SSRIs)such as paroxetine and citalopram have been shown to beminimally effective in patients with painful diabeticneuropathy.35,36Venlafaxine and duloxetine,serotonin-norepinephrine reuptake inhibitors(SNRIs),have alsobeen used to treat patients with neuropathic pain.37,38However,both SSRIs and SNRIs are associated with anincrease in arousals and awakenings as well as REMsuppression.39In healthy volunteers,duloxetine 60 and80mg seem to have an effect on sleep architecture that issimilar to other antidepressants.That is,it increased theonset latency and decreased the duration of REM sleep.Interestingly,the 2 doses had differing effects on sleepcontinuity,which was reduced with the 60-mg dose andimproved with the 80-mg dose.40Because of the effect ofSSRIs and SNRIs on sleep architecture and the fact thatthe analgesic effects of the SSRIs are not as pronouncedas those for TCAs,41a sedating TCA such as amitripty-line may be a better alternative in patients complaining ofpain and sleep disturbance.Possible adverse effects ofamitriptyline include daytime sedation,weight gain,arrhythmia,and anticholinergic side effects.42Anticonvulsants have been used to treat a variety ofneuropathic pain syndromes since the 1960s,whencarbamazepine was first reported to improve the sharplancinating pain associated with trigeminal neuralgia.43Presently,there are 3 anticonvulsant agents approved bythe US Food and Drug Administration for the treatmentofneuropathicpain:carbamazepinefortrigeminalneuralgia,gabapentin for