ETHICS

Chronic Pain in End-Stage Renal Disease

Sara 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

Epidemiology and Etiology

D ialysis is a successful life-sustaining ther-
apy for patients with end-stage renal dis-
ease (ESRD) with its effectiveness largely
judged by patient survival. However, as the
dialysis population ages and experiences mul-
tiple comorbidities, it will become increas-
ingly difficult to maintain a reasonable health-
related quality of life (HRQOL) for these
patients. A growing body of literature has
shown that pain is the most common symp-
tom for patients with ESRD impacting virtu-
ally every aspect of HRQOL and is the 1
symptom of greatest concern at the end of life.
Their chronic pain is typically moderate to
severe and is undertreated. For these reasons,
it is very important for nephrologists and fam-
ily physicians to master the principles of pain
assessment and management. Despite this,
there is a lack of clinical and research focus in
this area. This article will review the epidemi-
ology of chronic pain in ESRD, discuss basic
principles of pain assessment and manage-
ment, and highlight some of the challenges in
pain management in ESRD with the hope of
guiding health professionals in the effective
management of pain in patients with ESRD.
From the Division of Nephrology and Immunology, Uni-
versity of Alberta, Edmonton, Alberta, Canada.
Address correspondence to Sara N. Davison, MD, MHSc
(bioethics), FRCP(C), Division of Nephrology and Immunol-
ogy, University of Alberta, Edmonton, Alberta, Canada.
E-mail: sara.davison@ualberta.ca
© 2005 by the National Kidney Foundation, Inc.
1548-5595/05/1203-0009$30.00/0
doi:10.1053/j.ackd.2005.03.008
The International Association for the Study of
Pain defines pain as “an unpleasant sensory
and emotional experience associated with ac-
tual or potential tissue damage or described in
terms of such damage.”1 Epidemiologic data
of pain in ESRD are extremely limited; how-
ever, recent studies have shown that moderate
to severe chronic pain is common in ESRD.2-4
The literature suggests that 37% to 50% of
hemodialysis patients experience chronic pain
and that for 82% of these patients pain is
moderate to severe in intensity.2-4 Even in the
last day of life, pain is present in 42% of
patients withdrawing from dialysis.5
The etiology of pain may be from numer-
ous causes. Pain may be caused by comorbid-
ity, whereas dialysis sustains life, underlying
systemic diseases, and painful syndromes
such as ischemic limbs and neuropathies per-
sist. Given the aging dialysis population and
the increasing prevalence of comorbidites in-
cluding diabetes and hypertension, it is not
surprising that chronic pain is a particular
problem for patients with ESRD. Pain, how-
ever, may also be caused by ESRD itself. There
are numerous painful syndromes unique to
ESRD such as calciphylaxis and renal os-
teodystrophy that may develop during a pa-
tient’s time on dialysis. Pain may be a result of
the primary kidney disease itself (eg, polycys-
tic kidney disease) or the result of the treat-
ment of ESRD. Painful chronic infections such
as osteomyelitis and discitis are complications
from central lines, and arteriovenous fistulas
can lead to painful ischemic neuropathies. Re-
current pain caused by needle insertion, mus-
cle cramps, and headaches during dialysis

326 Advances in Chronic Kidney Disease, Vol 12, No 3 (July), 2005: pp 326-334
 Chronic Pain
treatments is perceived as chronic pain by
some patients.2
Despite limited data, it appears that mus-
culoskeletal pain is the most common of the
chronic pain syndromes in ESRD, as in the
general population.2 However, unlike the
general population, musculoskeletal pain in
ESRD is, on average, equal in severity to neu-
ropathic and ischemic pain. A synergistic ef-
fect of hyperparathyroidism and osteoarthritis
in the development of bone pain may contrib-
ute to the high prevalence and severity of
musculoskeletal pain in this population. How-
ever, the relative roles of osteoarthritis and
renal osteodystrophy in these chronic pain
syndromes of ESRD patients are not clear.
Given the diverse causes of pain in this pop-
ulation, it is not surprising that pain in dialy-
sis patients is often multifactorial. Distin-
guishing between the potential causes of pain
is important in determining optimal manage-
ment strategies. For example, neuropathic
pain is often difficult to control because it is
less responsive to strong opioids and com-
monly management requires adjuvants such
as antidepressants and anticonvulsants. The
synergistic interaction of these medications
with opioids is typically required for adequate
pain control.
Impact of Chronic Pain on Quality of
Life in Patients With ESRD
Pain is a multidimensional phenomenon with
physical, psychological, and social compo-
nents. Chronic pain is associated with psycho-
logical distress; impairment of interpersonal
relationships; excessive use of health care; sig-
nificant activity limitations in work, family
and social life; and adoption of a chronic sick
role.6,7 Recent research in ESRD suggests that
patient perceptions of physical symptoms, es-
pecially pain, are associated with depression
and insomnia and may be more important
than objective assessments in determining the
HRQOL of patients with ESRD.2,8,9 The term
“total” pain10 refers to any unmet needs of the
patient that may aggravate pain and captures
the importance of all the following interac-
tions: physical, emotional (anxiety and de-
pression), social (isolation and abandonment),
spiritual (search for meaning and purpose),
327
and financial (fear of burdening the family).11
The pain threshold and response to pain ther-
apy largely depend on these patient-related
factors rather than the potency of analgesics.
These psychosocial and spiritual issues enter
into a vicious cycle of interacting with and
perpetuating physical symptoms and suffer-
ing of the patient. This underlines the need to
address the psychosocial and spiritual issues
as well as the physical in pain management.
Current Pharmacologic Management in
ESRD
Pain in ESRD is inadequately managed, and,
despite what appears to be an increasing prev-
alence of chronic pain, analgesic use has de-
creased over the last few years. The Dialysis
Outcomes and Practice Patterns Study com-
pared analgesic use from 1997 to 2000 for
3,749 patients in 142 United States facilities.12
The percentage of patients using any analgesic
decreased from 30% to 24%. Narcotic use de-
creased from 18% to less than 15%, and acet-
aminophen use decreased from 11% to 6%. In
this study, 74% of patients with pain that
interfered with work had no analgesic pre-
scription. These findings are consistent with
other reports in which 35% of hemodialysis
patients with chronic pain were not pre-
scribed analgesics, despite the vast majority
experiencing moderate or severe pain and less
than 10% were prescribed strong opioids.2
Barriers to Pain Assessment and
Management in ESRD
Inadequate pain management is not unique to
nephrology. Despite the availability of effec-
tive pain management interventions13 and
published guidelines14 for the management of
malignant and nonmalignant pain, many pa-
tients continue to receive inadequate analge-
sia.15 Patient-related factors are a major issue.
Patients fail to seek medical attention until
pain becomes severe. They think they need
analgesics, especially strong opioids, only
“when absolutely necessary.” Fear of addic-
tion is also common. Some patients stop tak-
ing opioids because adverse effects such as
nausea and vomiting are mistaken for an al-
lergic reaction. Inadequate pain assessment
328 Sara N. Davison
and lack of staff time and training in the basic
principles of pain management have also been
identified as barriers to adequate pain man-
agement in cancer patients.16 These barriers
also apply to ESRD; however, there are
unique barriers that must be overcome in pa-
tients with ESRD. There is a lack of recogni-
tion by the nephrology community concern-
ing the extent and severity of the problem and
hence a lack of clinical and research focus in
this area. This has led to a lack of a discrete
medical literature that synthesizes pain man-
agement and nephrology. Probably one of the
largest obstacles is the altered pharmacokinet-
ics and pharmacodynamics of analgesics in
ESRD. This will be addressed in more detail
later. The high incidence of comorbidity,
polypharmacy, and an elderly population also
complicate pain management because of in-
creased risk of toxicity and adverse effects of
analgesics. In addition, the adverse effects of
analgesics may be mimicked by uremic symp-
toms resulting in the withdrawal of analgesia.
Finally, there is a distinct lack of training in
pain assessment and management in nephrol-
ogy training programs.
Pharmacokinetics of Opioids in ESRD
Poor management of pain in ESRD is in large
part because of the reluctance to use analge-
sics and, in particular, opioids. The absorp-
tion, metabolism, and clearance of analgesics
are more complex in ESRD with patients be-
ing more likely to experience opioid toxicity.
Unfortunately, the pharmacokinetics and
pharmacodynamics of opioids have yet to be
studied in patients with ESRD; therefore, the
appropriate dosing of opioids in ESRD re-
mains unknown. Effective treatment of pain
in ESRD requires a clear understanding of the
pharmacology, potential impact, and adverse
effects associated with each of the analgesics
used. Until the pharmacokinetics and phar-
macodynamics of analgesics in ESRD are
studied, their use will likely remain limited in
this population with inadequate pain control.
Most of the information about opioid use in
ESRD patients comes from experience with
morphine. Clinical data suggest that patients
with kidney failure are particularly suscepti-
ble to the toxic effects of morphine. Nausea,
vomiting, myoclonus, and seizures as well as
prolonged and profound analgesia, sedation,
and respiratory depression have been re-
ported with morphine in patients suffering
from kidney failure.17-21 There are several hy-
potheses for this including increased entero-
hepatic circulation of morphine and accumu-
lation of large quantities of the active
metabolites morphine-6-glucuronide (M6G)
and morphine-3-glucuronide (M3G).22 Be-
cause of these difficulties, alternative strong
opioids are typically recommended to manage
severe pain in patients with ESRD. It has been
suggested that other opioids such hydromor-
phone, methadone, and fentanyl are better
tolerated with safer profiles in this patient
population. Data, however, remain limited
with these opioids and the evidence is anec-
dotal at best.
Hydromorphone
Hydromorphone may potentially be an unde-
rused opioid in treating severe pain in ESRD
patients. It is a hydrogenated ketone of mor-
phine with approximately 7 times the narcotic
analgesic effect of morphine and produces
significant and rapid pain relief after oral ad-
ministration.23-25 It has a similar side effect
profile to morphine,26 although it may cause
less pruritus, sedation, and nausea.27 What
few data are available on oral hydromor-
phone come from single dose studies in
healthy subjects. It has a short half-life and is
extensively metabolized to hydromorphone-
3-glucuronide (H3G) in the liver with the con-
jugates excreted in the urine. In addition,
small amounts of hydromorphone-6-glucuro-
nide (H6G) are produced. Given the structural
similarity of H3G and H6G to M3G and M6G
respectively, one could expect these metabo-
lites to accumulate in patients with kidney
failure. There is a single report in the literature
in which 1 patient with chronic kidney failure
(Cr 327 ␮mol/L) who had received hydro-
morphone 24 mg daily had a 4-fold increase in
the molar ratio of H3G to hydromorphone.28
This is supported by the occasional clinical
observation in the literature resulting in neu-
roexcitation29 and cognitive impairment.30
Despite theoretical concerns, a recent retro-
spective audit31 and our own clinical experi-
 Chronic Pain
ence suggest that hydromorphone may be bet-
ter tolerated than morphine by patients with
ESRD.
Methadone
Methadone, a synthetic opioid derivative, is a
powerful mu-delta opioid agonist.32 The mol-
ecule also blocks N-methyl-D-aspartate recep-
tor sites.33 This has been shown to decrease
the formation of opioid tolerance and prevent
glutamate excitotoxicity, which has been im-
plicated in the pathogenesis of chronic pain.34
Clinically, its main use has been as a substi-
tute opioid in the management of depen-
dence. However, methadone is increasingly
being used as an effective opioid in the man-
agement of nonmalignant and cancer pain,35
where some clinicians believe it may be more
effective for neuropathic pain than other
strong opioids because of its N-methyl-D-as-
partate receptor antagonism.36,37 Methadone
has high oral bioavailability and is extensively
distributed in the tissues where it accumulates
with repeated dosing. Thus, although it has a
plasma half-life of 2 to 3 hours, it has pro-
longed pharmacological action because of
slow release from the reservoirs in the tissues
of up to 60 hours.38 Methadone is excreted
mainly in the feces with metabolism into
pharmacologically inactive metabolites pri-
marily in the liver, although about 20% is
excreted unchanged in the urine.39 It does not
appear to be removed by dialysis,40,41 and, in
anuric patients, methadone excretion in the
feces may be enhanced with limited accumu-
lation in plasma.41 These factors suggest that
methadone may be an effective analgesic for
use in patients with kidney impairment if
carefully monitored, although extensive phar-
macokinetic and pharmacologic data are not
yet available.
Fentanyl
Fentanyl is a rapid-onset, potent, synthetic
opioid commonly given to produce analgesia
during anesthesia.42 Fentanyl is 50 to 100
times more potent and 1,000 times more li-
pophilic than morphine.43 These properties
make it suitable for use in a transdermal de-
livery system.44 Fentanyl causes less hista-
329
mine release, a lower incidence of constipa-
tion and affords greater cardiovascular
stability than morphine and can thus be a
useful alternative when the side effects of
morphine hamper effective pain manage-
ment.43 Fentanyl is rapidly metabolized in the
liver with only 5% to 10% excreted unchanged
in the urine.45 Its metabolites are considered
to be inactive. It is often assumed that because
fentanyl is metabolized and eliminated almost
exclusively by the liver, its kinetics would be
minimally altered by kidney failure. How-
ever, the hepatic clearance and extraction of
drugs with high hepatic extraction ratios like
fentanyl can be inhibited by uremia.46,47 There
are very few pharmacokinetic data on fenta-
nyl in ESRD, and these are limited to intrave-
nous use during anesthesia.46-50 These studies
have conflicting data about the effect of kid-
ney failure on the elimination and distribution
of fentanyl. One study showed a strong in-
verse correlation between the clearance of fen-
tanyl and the blood urea nitrogen.46 However,
this was not duplicated in 2 small studies and
a case study.48-50
These conflicting and limited data make
dosing of opioids difficult in ESRD and have
reduced significantly their potential use in this
population. An expanded understanding of
the pharmacokinetics and pharmacodynamics
of opioids in ESRD will be required to develop
effective clinical approaches to pain syn-
dromes in ESRD.
Pharmacologic Management of
Chronic Pain in ESRD
Given the lack of pharmacokinetic and phar-
macodynamic data, it is difficult to confi-
dently advocate for specific treatment algo-
rithms for pain management in ESRD.
However, there are principles of pain assess-
ment and management that can be adapted
and integrated into the care of ESRD patients
while further research tests the effectiveness
of various pharmacological and nonpharma-
cological interventions. These basic principles
of pain management are summarized in Fig-
ure 1 with some points expanded on later.
One of the first principles of pain manage-
ment is to believe the patient’s report of pain
and initiate discussions about their pain. Clin-
330 Sara N. Davison

Figure 1. Fast facts on pain assessment and management.

ically, it is important to differentiate patients ple function quite effectively with a back-
with recurrent or persistent pain who remain ground of mild pain that does not seriously
functional from those whose pain produces impair or distract them. As pain severity in-
significant disability and suffering. Many peo- creases to moderate intensity, pain passes a
 Chronic Pain 331

Figure 1. (Cont’d).

threshold beyond which it is hard for the
patient to ignore. At this point, it becomes
disruptive to many aspects of the patient’s
life.51 This severity-interference relationship
can be defined on a 0- to 10-point numerical
scale where 1 to 4 represents mild pain, 5 to 6
represents moderate pain, and 7 to 10 repre-
sents severe pain. The World Health Organi-
zation analgesic ladder for pain management
(Fig 2) is predicated on classifying pain into
one of these severity categories. It is not al-
ways possible to completely eliminate pain. A
more realistic goal of pain management may
be to optimize pain relief while focusing on
disability issues to make patients more func-
tional in their daily activities. The reduction of
pain severity across the severity boundaries
might be thought of as clinically significant
goals of therapy that could help achieve this
aim.
332 Sara N. Davison
Figure 2. The World Health Organization ladder.
The selection of analgesics should take into
account the type and severity of pain, antici-
pated duration of treatment, and potential ad-
verse effects or interactions with concomitant
medications. Reviews of the available evidence
on analgesia in patients with ESRD have been
recently published, including suggested dosing
regimens.52,53 The World Health Organization
advocates a stepwise approach to analgesic
therapy (Fig 2). The first step is to use agents
such as acetaminophen or nonsteroidal anti-
inflammatory drugs (NSAIDs) for mild to mod-
erate pain. Acetaminophen is metabolized by
the liver and does not require dose adjustment
in the presence of ESRD. Acetaminophen is
found in numerous over-the-counter medica-
tions. Inadvertent use of multiple acetamino-
phen-containing medications may result in hep-
atotoxicity. The National Kidney Foundation
recommends acetaminophen as the nonnarcotic
analgesic of choice for mild to moderate pain for
patients with ESRD.54 NSAIDs can be used for
the treatment of mild to moderate pain and can
be used in conjunction with acetaminophen.
NSAIDs may increase the risk of bleeding in
patients with ESRD because of their effects on
platelet function and gastrointestinal mucosa
and may have potential cardiovascular risks.
For these reasons, NSAIDs should be used for
precise indications (eg, gout) and for a limited
time in patients with ESRD. NSAIDs may also
compromise residual kidney function; residual
kidney function is associated with overall well-
being and survival and should be protected as
much as possible. Step 2 involves weak opioids
for the initial treatment of moderate to severe
pain or if pain control is inadequate with a lesser
analgesic. If pain is still not relieved, or if it is
severe, step 3 advocates for a stronger opioid
such as hydromorphone. Opioids may be
switched from one to another if adequate pain
control occurs at a dose that results in trouble-
some adverse effects. Cross tolerance to the ad-
verse effects of opioids may allow a switch to
another opioid that can give equally good pain
control but at a dose that does not cause the
adverse effects. Adjuvants may be used at any
step of the ladder for specific indications. Low-
er-level analgesics can be used for breakthrough
analgesia while using regular doses of higher-
level analgesics. Common adverse effects of opi-
oids such as constipation should be anticipated
and actively prevented. This is especially impor-
tant in peritoneal dialysis patients in whom con-
stipation interferes with functioning of the peri-
toneal dialysis catheter.
Due to altered pharmacokinetics and phar-
macodynamics, there are analgesics such as
meperidine and propoxyphene that should be
never be used in ESRD patients. Meperidine is
metabolized in the liver to the active metabo-
lite normeperidine which is excreted by the
kidneys. Meperidine and normeperidine are
associated with seizures in ESRD and should
not be used in this patient population. The
Dialysis Outcomes and Practice Patterns
Study recently reported that propoxyphene is
the most commonly prescribed opioid and
that it was prescribed alone or in combination
with acetaminophen for 50.7% of patients.12
Propoxyphene is related to methadone, and
its active metabolite norpropoxyphene is ex-
creted by the kidney. It has properties similar
to quinine and can predispose patients to
cardiac conduction abnormalities. Neither
propoxyphene nor norpropoxyphene are re-
moved with dialysis, and the cardiotoxicity
cannot be reversed by naloxone. It should be
avoided or used with extreme caution in pa-
tients with ESRD. Opioids known to accumu-
late with chronic use such as morphine can
still be safely and effectively used in acute
pain situations; they should be switched to
safer analgesics for more long-term pain man-
agement.
Understanding the cause of pain is critical
 Chronic Pain
in tailoring analgesic therapy. Somatic pain,
such as pain associated with bone disease,
responds well to NSAIDs and opioids. Con-
trol of neuropathic pain is often difficult be-
cause patients are less responsive to strong
opioids. Adjuvants such as antidepressants
and anticonvulsants are typically required for
adequate pain control. Amitriptyline is effec-
tive in neuropathic pain; it takes less time to
achieve analgesia than it does to control de-
pression.
Summary
Chronic pain is a common and disabling
symptom for patients with ESRD that is cur-
rently being undertreated. Effective pain man-
agement is an integral component of quality
care for our patients. Unless the psychosocial,
spiritual, and physical attributes of pain are
all addressed, pain will never be relieved ad-
equately.
Nephrology practices are frequently de-
pendent on protocols aimed at guiding and
assuring quality assessment and improve-
ment. These protocols have largely focused on
optimizing biochemical parameters. The use
of such protocols has been widely accepted as
a necessity in attaining improved medical out-
comes. Pain assessment and management pro-
tocols need to be developed and implemented
in the dialysis units to both guide staff in the
practices of pain assessment and management
and to allow for routine symptom assessment
and management. Because dialysis is rou-
tinely delivered in a team-based setting, it is
perfectly situated to adopt the interdiscipli-
nary team model that is common to palliative
care, a model that provides excellent symp-
tom management and quality of life assess-
ment.55 However, for these algorithms to be
developed, an increased clinical and research
focus in this area is required. The pharmaco-
kinetics and various intervention strategies
will need to be systematically studied in the
ESRD population.
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