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hronic Pain in End-Stage Renal Diseaseara N. Davison

A growing body of literature has shown that chronic pain is common for patients with end-stage renal

disease (ESRD), is typically moderate or severe, and impacts virtually every aspect of health-related

quality of life. Unfortunately, there is a lack of clinical and research focus in this area in nephrology,

and pain in ESRD is undertreated. This article will review the epidemiology of chronic pain in ESRD,

discuss basic principles of pain assessment and management, and highlight some of the challenges

in pain management in ESRD with the hope of guiding health professionals in the effective manage-

ment of pain in patients with ESRD.

© 2005 by the National Kidney Foundation, Inc.

Index Words: Pain; pain management; hemodialysis; analgesics; opioids

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ialysis is a successful life-sustaining ther-apy for patients with end-stage renal dis-

ase (ESRD) with its effectiveness largelyudged by patient survival. However, as theialysis population ages and experiences mul-

iple comorbidities, it will become increas-ngly difficult to maintain a reasonable health-elated quality of life (HRQOL) for theseatients. A growing body of literature hashown that pain is the most common symp-om for patients with ESRD impacting virtu-lly every aspect of HRQOL and is the 1ymptom of greatest concern at the end of life.heir chronic pain is typically moderate toevere and is undertreated. For these reasons,t is very important for nephrologists and fam-ly physicians to master the principles of painssessment and management. Despite this,here is a lack of clinical and research focus inhis area. This article will review the epidemi-logy of chronic pain in ESRD, discuss basicrinciples of pain assessment and manage-ent, and highlight some of the challenges in

ain management in ESRD with the hope ofuiding health professionals in the effectiveanagement of pain in patients with ESRD.

From the Division of Nephrology and Immunology, Uni-ersity of Alberta, Edmonton, Alberta, Canada.

Address correspondence to Sara N. Davison, MD, MHScbioethics), FRCP(C), Division of Nephrology and Immunol-gy, University of Alberta, Edmonton, Alberta, Canada.-mail: sara.davison@ualberta.ca

© 2005 by the National Kidney Foundation, Inc.1548-5595/05/1203-0009$30.00/0

cdoi:10.1053/j.ackd.2005.03.008

Advances in Chronic Kidney Disease, Vol26

pidemiology and Etiology

he International Association for the Study ofain defines pain as “an unpleasant sensorynd emotional experience associated with ac-ual or potential tissue damage or described inerms of such damage.”1 Epidemiologic dataf pain in ESRD are extremely limited; how-ver, recent studies have shown that moderateo severe chronic pain is common in ESRD.2-4

he literature suggests that 37% to 50% ofemodialysis patients experience chronic painnd that for 82% of these patients pain isoderate to severe in intensity.2-4 Even in the

ast day of life, pain is present in 42% ofatients withdrawing from dialysis.5

The etiology of pain may be from numer-us causes. Pain may be caused by comorbid-

ty, whereas dialysis sustains life, underlyingystemic diseases, and painful syndromesuch as ischemic limbs and neuropathies per-ist. Given the aging dialysis population andhe increasing prevalence of comorbidites in-luding diabetes and hypertension, it is noturprising that chronic pain is a particularroblem for patients with ESRD. Pain, how-ver, may also be caused by ESRD itself. Therere numerous painful syndromes unique toSRD such as calciphylaxis and renal os-

eodystrophy that may develop during a pa-ient’s time on dialysis. Pain may be a result ofhe primary kidney disease itself (eg, polycys-ic kidney disease) or the result of the treat-

ent of ESRD. Painful chronic infections suchs osteomyelitis and discitis are complicationsrom central lines, and arteriovenous fistulasan lead to painful ischemic neuropathies. Re-urrent pain caused by needle insertion, mus-

le cramps, and headaches during dialysis

12, No 3 (July), 2005: pp 326-334

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327Chronic Pain

reatments is perceived as chronic pain byome patients.2

Despite limited data, it appears that mus-uloskeletal pain is the most common of thehronic pain syndromes in ESRD, as in theeneral population.2 However, unlike theeneral population, musculoskeletal pain inSRD is, on average, equal in severity to neu-opathic and ischemic pain. A synergistic ef-ect of hyperparathyroidism and osteoarthritisn the development of bone pain may contrib-te to the high prevalence and severity ofusculoskeletal pain in this population. How-

ver, the relative roles of osteoarthritis andenal osteodystrophy in these chronic painyndromes of ESRD patients are not clear.iven the diverse causes of pain in this pop-lation, it is not surprising that pain in dialy-is patients is often multifactorial. Distin-uishing between the potential causes of pain

s important in determining optimal manage-ent strategies. For example, neuropathic

ain is often difficult to control because it isess responsive to strong opioids and com-

only management requires adjuvants suchs antidepressants and anticonvulsants. Theynergistic interaction of these medicationsith opioids is typically required for adequateain control.

mpact of Chronic Pain on Quality ofife in Patients With ESRD

ain is a multidimensional phenomenon withhysical, psychological, and social compo-ents. Chronic pain is associated with psycho-

ogical distress; impairment of interpersonalelationships; excessive use of health care; sig-ificant activity limitations in work, familynd social life; and adoption of a chronic sickole.6,7 Recent research in ESRD suggests thatatient perceptions of physical symptoms, es-ecially pain, are associated with depressionnd insomnia and may be more importanthan objective assessments in determining the

RQOL of patients with ESRD.2,8,9 The termtotal” pain10 refers to any unmet needs of theatient that may aggravate pain and captures

he importance of all the following interac-ions: physical, emotional (anxiety and de-ression), social (isolation and abandonment),

piritual (search for meaning and purpose), l

nd financial (fear of burdening the family).11

he pain threshold and response to pain ther-py largely depend on these patient-relatedactors rather than the potency of analgesics.hese psychosocial and spiritual issues enter

nto a vicious cycle of interacting with anderpetuating physical symptoms and suffer-

ng of the patient. This underlines the need toddress the psychosocial and spiritual issuess well as the physical in pain management.

urrent Pharmacologic Management inSRD

ain in ESRD is inadequately managed, and,espite what appears to be an increasing prev-lence of chronic pain, analgesic use has de-reased over the last few years. The Dialysisutcomes and Practice Patterns Study com-ared analgesic use from 1997 to 2000 for,749 patients in 142 United States facilities.12

he percentage of patients using any analgesicecreased from 30% to 24%. Narcotic use de-reased from 18% to less than 15%, and acet-minophen use decreased from 11% to 6%. Inhis study, 74% of patients with pain thatnterfered with work had no analgesic pre-cription. These findings are consistent withther reports in which 35% of hemodialysisatients with chronic pain were not pre-cribed analgesics, despite the vast majorityxperiencing moderate or severe pain and lesshan 10% were prescribed strong opioids.2

arriers to Pain Assessment andanagement in ESRD

nadequate pain management is not unique toephrology. Despite the availability of effec-

ive pain management interventions13 andublished guidelines14 for the management ofalignant and nonmalignant pain, many pa-

ients continue to receive inadequate analge-ia.15 Patient-related factors are a major issue.atients fail to seek medical attention untilain becomes severe. They think they neednalgesics, especially strong opioids, onlywhen absolutely necessary.” Fear of addic-ion is also common. Some patients stop tak-ng opioids because adverse effects such asausea and vomiting are mistaken for an al-

ergic reaction. Inadequate pain assessment

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328 Sara N. Davison

nd lack of staff time and training in the basicrinciples of pain management have also been

dentified as barriers to adequate pain man-gement in cancer patients.16 These barrierslso apply to ESRD; however, there arenique barriers that must be overcome in pa-

ients with ESRD. There is a lack of recogni-ion by the nephrology community concern-ng the extent and severity of the problem andence a lack of clinical and research focus in

his area. This has led to a lack of a discreteedical literature that synthesizes pain man-

gement and nephrology. Probably one of theargest obstacles is the altered pharmacokinet-cs and pharmacodynamics of analgesics inSRD. This will be addressed in more detail

ater. The high incidence of comorbidity,olypharmacy, and an elderly population alsoomplicate pain management because of in-reased risk of toxicity and adverse effects ofnalgesics. In addition, the adverse effects ofnalgesics may be mimicked by uremic symp-oms resulting in the withdrawal of analgesia.inally, there is a distinct lack of training inain assessment and management in nephrol-gy training programs.

harmacokinetics of Opioids in ESRD

oor management of pain in ESRD is in largeart because of the reluctance to use analge-ics and, in particular, opioids. The absorp-ion, metabolism, and clearance of analgesicsre more complex in ESRD with patients be-ng more likely to experience opioid toxicity.nfortunately, the pharmacokinetics andharmacodynamics of opioids have yet to betudied in patients with ESRD; therefore, theppropriate dosing of opioids in ESRD re-ains unknown. Effective treatment of pain

n ESRD requires a clear understanding of theharmacology, potential impact, and adverseffects associated with each of the analgesicssed. Until the pharmacokinetics and phar-acodynamics of analgesics in ESRD are

tudied, their use will likely remain limited inhis population with inadequate pain control.

Most of the information about opioid use inSRD patients comes from experience withorphine. Clinical data suggest that patientsith kidney failure are particularly suscepti-

le to the toxic effects of morphine. Nausea, s

omiting, myoclonus, and seizures as well asrolonged and profound analgesia, sedation,nd respiratory depression have been re-orted with morphine in patients suffering

rom kidney failure.17-21 There are several hy-otheses for this including increased entero-epatic circulation of morphine and accumu-

ation of large quantities of the activeetabolites morphine-6-glucuronide (M6G)

nd morphine-3-glucuronide (M3G).22 Be-ause of these difficulties, alternative strongpioids are typically recommended to manageevere pain in patients with ESRD. It has beenuggested that other opioids such hydromor-hone, methadone, and fentanyl are better

olerated with safer profiles in this patientopulation. Data, however, remain limitedith these opioids and the evidence is anec-otal at best.

ydromorphone

ydromorphone may potentially be an unde-used opioid in treating severe pain in ESRDatients. It is a hydrogenated ketone of mor-hine with approximately 7 times the narcoticnalgesic effect of morphine and producesignificant and rapid pain relief after oral ad-inistration.23-25 It has a similar side effect

rofile to morphine,26 although it may causeess pruritus, sedation, and nausea.27 Whatew data are available on oral hydromor-hone come from single dose studies inealthy subjects. It has a short half-life and isxtensively metabolized to hydromorphone--glucuronide (H3G) in the liver with the con-

ugates excreted in the urine. In addition,mall amounts of hydromorphone-6-glucuro-ide (H6G) are produced. Given the structuralimilarity of H3G and H6G to M3G and M6Gespectively, one could expect these metabo-ites to accumulate in patients with kidneyailure. There is a single report in the literaturen which 1 patient with chronic kidney failureCr 327 �mol/L) who had received hydro-

orphone 24 mg daily had a 4-fold increase inhe molar ratio of H3G to hydromorphone.28

his is supported by the occasional clinicalbservation in the literature resulting in neu-oexcitation29 and cognitive impairment.30

espite theoretical concerns, a recent retro-

pective audit31 and our own clinical experi-

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329Chronic Pain

nce suggest that hydromorphone may be bet-er tolerated than morphine by patients withSRD.

ethadone

ethadone, a synthetic opioid derivative, is aowerful mu-delta opioid agonist.32 The mol-cule also blocks N-methyl-D-aspartate recep-or sites.33 This has been shown to decreasehe formation of opioid tolerance and preventlutamate excitotoxicity, which has been im-licated in the pathogenesis of chronic pain.34

linically, its main use has been as a substi-ute opioid in the management of depen-ence. However, methadone is increasinglyeing used as an effective opioid in the man-gement of nonmalignant and cancer pain,35

here some clinicians believe it may be moreffective for neuropathic pain than othertrong opioids because of its N-methyl-D-as-artate receptor antagonism.36,37 Methadoneas high oral bioavailability and is extensivelyistributed in the tissues where it accumulatesith repeated dosing. Thus, although it has alasma half-life of 2 to 3 hours, it has pro-

onged pharmacological action because oflow release from the reservoirs in the tissuesf up to 60 hours.38 Methadone is excretedainly in the feces with metabolism into

harmacologically inactive metabolites pri-arily in the liver, although about 20% is

xcreted unchanged in the urine.39 It does notppear to be removed by dialysis,40,41 and, innuric patients, methadone excretion in theeces may be enhanced with limited accumu-ation in plasma.41 These factors suggest that

ethadone may be an effective analgesic forse in patients with kidney impairment ifarefully monitored, although extensive phar-acokinetic and pharmacologic data are not

et available.

entanyl

entanyl is a rapid-onset, potent, syntheticpioid commonly given to produce analgesiauring anesthesia.42 Fentanyl is 50 to 100

imes more potent and 1,000 times more li-ophilic than morphine.43 These propertiesake it suitable for use in a transdermal de-

ivery system.44 Fentanyl causes less hista- a

ine release, a lower incidence of constipa-ion and affords greater cardiovasculartability than morphine and can thus be aseful alternative when the side effects oforphine hamper effective pain manage-ent.43 Fentanyl is rapidly metabolized in the

iver with only 5% to 10% excreted unchangedn the urine.45 Its metabolites are consideredo be inactive. It is often assumed that becauseentanyl is metabolized and eliminated almostxclusively by the liver, its kinetics would beinimally altered by kidney failure. How-

ver, the hepatic clearance and extraction ofrugs with high hepatic extraction ratios like

entanyl can be inhibited by uremia.46,47 Therere very few pharmacokinetic data on fenta-yl in ESRD, and these are limited to intrave-ous use during anesthesia.46-50 These studiesave conflicting data about the effect of kid-ey failure on the elimination and distributionf fentanyl. One study showed a strong in-erse correlation between the clearance of fen-anyl and the blood urea nitrogen.46 However,his was not duplicated in 2 small studies and

case study.48-50

These conflicting and limited data makeosing of opioids difficult in ESRD and haveeduced significantly their potential use in thisopulation. An expanded understanding of

he pharmacokinetics and pharmacodynamicsf opioids in ESRD will be required to developffective clinical approaches to pain syn-romes in ESRD.

harmacologic Management ofhronic Pain in ESRD

iven the lack of pharmacokinetic and phar-acodynamic data, it is difficult to confi-

ently advocate for specific treatment algo-ithms for pain management in ESRD.owever, there are principles of pain assess-ent and management that can be adapted

nd integrated into the care of ESRD patientshile further research tests the effectiveness

f various pharmacological and nonpharma-ological interventions. These basic principlesf pain management are summarized in Fig-re 1 with some points expanded on later.

One of the first principles of pain manage-ent is to believe the patient’s report of pain

nd initiate discussions about their pain. Clin-

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330 Sara N. Davison

cally, it is important to differentiate patientsith recurrent or persistent pain who remain

unctional from those whose pain produces

Figure 1. Fast facts on pain

ignificant disability and suffering. Many peo- c

le function quite effectively with a back-round of mild pain that does not seriously

mpair or distract them. As pain severity in-

ssment and management.

reases to moderate intensity, pain passes a

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hreshold beyond which it is hard for theatient to ignore. At this point, it becomesisruptive to many aspects of the patient’s

ife.51 This severity-interference relationshipan be defined on a 0- to 10-point numericalcale where 1 to 4 represents mild pain, 5 to 6epresents moderate pain, and 7 to 10 repre-ents severe pain. The World Health Organi-ation analgesic ladder for pain management

Figure

Fig 2) is predicated on classifying pain into a

ne of these severity categories. It is not al-ays possible to completely eliminate pain. Aore realistic goal of pain management may

e to optimize pain relief while focusing onisability issues to make patients more func-

ional in their daily activities. The reduction ofain severity across the severity boundariesight be thought of as clinically significant

oals of therapy that could help achieve this

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The selection of analgesics should take intoccount the type and severity of pain, antici-ated duration of treatment, and potential ad-erse effects or interactions with concomitantedications. Reviews of the available evidence

n analgesia in patients with ESRD have beenecently published, including suggested dosingegimens.52,53 The World Health Organizationdvocates a stepwise approach to analgesicherapy (Fig 2). The first step is to use agentsuch as acetaminophen or nonsteroidal anti-nflammatory drugs (NSAIDs) for mild to mod-rate pain. Acetaminophen is metabolized byhe liver and does not require dose adjustmentn the presence of ESRD. Acetaminophen isound in numerous over-the-counter medica-ions. Inadvertent use of multiple acetamino-hen-containing medications may result in hep-totoxicity. The National Kidney Foundationecommends acetaminophen as the nonnarcoticnalgesic of choice for mild to moderate pain foratients with ESRD.54 NSAIDs can be used for

he treatment of mild to moderate pain and cane used in conjunction with acetaminophen.SAIDs may increase the risk of bleeding inatients with ESRD because of their effects onlatelet function and gastrointestinal mucosand may have potential cardiovascular risks.or these reasons, NSAIDs should be used forrecise indications (eg, gout) and for a limited

ime in patients with ESRD. NSAIDs may alsoompromise residual kidney function; residualidney function is associated with overall well-

igure 2. The World Health Organization ladder.

eing and survival and should be protected as

uch as possible. Step 2 involves weak opioidsor the initial treatment of moderate to severeain or if pain control is inadequate with a lessernalgesic. If pain is still not relieved, or if it isevere, step 3 advocates for a stronger opioiduch as hydromorphone. Opioids may bewitched from one to another if adequate painontrol occurs at a dose that results in trouble-ome adverse effects. Cross tolerance to the ad-erse effects of opioids may allow a switch tonother opioid that can give equally good painontrol but at a dose that does not cause thedverse effects. Adjuvants may be used at anytep of the ladder for specific indications. Low-r-level analgesics can be used for breakthroughnalgesia while using regular doses of higher-evel analgesics. Common adverse effects of opi-ids such as constipation should be anticipatednd actively prevented. This is especially impor-ant in peritoneal dialysis patients in whom con-tipation interferes with functioning of the peri-oneal dialysis catheter.

Due to altered pharmacokinetics and phar-acodynamics, there are analgesics such aseperidine and propoxyphene that should be

ever be used in ESRD patients. Meperidine isetabolized in the liver to the active metabo-

ite normeperidine which is excreted by theidneys. Meperidine and normeperidine aressociated with seizures in ESRD and shouldot be used in this patient population. Theialysis Outcomes and Practice Patternstudy recently reported that propoxyphene ishe most commonly prescribed opioid andhat it was prescribed alone or in combination

ith acetaminophen for 50.7% of patients.12

ropoxyphene is related to methadone, andts active metabolite norpropoxyphene is ex-reted by the kidney. It has properties similaro quinine and can predispose patients toardiac conduction abnormalities. Neitherropoxyphene nor norpropoxyphene are re-oved with dialysis, and the cardiotoxicity

annot be reversed by naloxone. It should bevoided or used with extreme caution in pa-ients with ESRD. Opioids known to accumu-ate with chronic use such as morphine cantill be safely and effectively used in acuteain situations; they should be switched toafer analgesics for more long-term pain man-gement.

Understanding the cause of pain is critical

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333Chronic Pain

n tailoring analgesic therapy. Somatic pain,uch as pain associated with bone disease,esponds well to NSAIDs and opioids. Con-rol of neuropathic pain is often difficult be-ause patients are less responsive to strongpioids. Adjuvants such as antidepressantsnd anticonvulsants are typically required fordequate pain control. Amitriptyline is effec-ive in neuropathic pain; it takes less time tochieve analgesia than it does to control de-ression.

ummary

hronic pain is a common and disablingymptom for patients with ESRD that is cur-ently being undertreated. Effective pain man-gement is an integral component of qualityare for our patients. Unless the psychosocial,piritual, and physical attributes of pain arell addressed, pain will never be relieved ad-quately.

Nephrology practices are frequently de-endent on protocols aimed at guiding andssuring quality assessment and improve-ent. These protocols have largely focused on

ptimizing biochemical parameters. The usef such protocols has been widely accepted asnecessity in attaining improved medical out-

omes. Pain assessment and management pro-ocols need to be developed and implementedn the dialysis units to both guide staff in theractices of pain assessment and managementnd to allow for routine symptom assessmentnd management. Because dialysis is rou-inely delivered in a team-based setting, it iserfectly situated to adopt the interdiscipli-ary team model that is common to palliativeare, a model that provides excellent symp-om management and quality of life assess-

ent.55 However, for these algorithms to beeveloped, an increased clinical and research

ocus in this area is required. The pharmaco-inetics and various intervention strategiesill need to be systematically studied in theSRD population.

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