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Journal Of Pain & Palliative Care Pharmacotherapy

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The Use of Opioid Analgesia in End-Stage Renal Disease Patients Managed

Without Dialysis
Fliss E. M. Murtagh a; Mee-Onn Chai b; Paul Donohoe b; Polly M. Edmonds b; Irene J. Higginson a
a
Department of Palliative Care & Policy, Kings College, London b Kings College Hospital, London
Online Publication Date: 06 June 2007

To cite this Article Murtagh, Fliss E. M., Chai, Mee-Onn, Donohoe, Paul, Edmonds, Polly M. and Higginson, Irene J.(2007)'The Use of

Opioid Analgesia in End-Stage Renal Disease Patients Managed Without Dialysis',Journal Of Pain & Palliative Care
Pharmacotherapy,21:2,5 16
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ARTICLES

The Use of Opioid Analgesia

in End-Stage Renal Disease Patients Managed
Without Dialysis:
Recommendations for Practice
Fliss E. M. Murtagh
Mee-Onn Chai
Paul Donohoe
Polly M. Edmonds
Irene J. Higginson

ABSTRACT. The numbers of patients dying with end-stage renal disease (ESRD), particularly
those managed conservatively (without dialysis) or withdrawing from dialysis is increasing rapidly in developed countries. There is growing awareness of the extensive symptom control needs
of these patients. Pain is a common problem, and has been both under-recognized and under-treated. It is challenging to manage, largely because of the constraints very poor renal function
places on use of medication. Although pharmacological reviews of opioid use in renal failure have
been published, there is a need for clinical recommendations to aid palliative and renal specialists
in providing effective pain control. This review describes the pharmacological evidence for and
against the use of the different opioid medications, and translates this into clinical recommendations for ESRD patients managed conservatively, not for those on dialysis for whom there are different pharmacological considerations. Acetaminophen (paracetamol) is recommended at Step 1
of the World Health Organization ladder. Of the Step 2 analgesics, tramadol is the least problematic, although dose reduction and increased dosing interval are required, and caution should be exercised. Of the Step 3 analgesics, fentanyl, alfentanil and methadone are recommended. There is
limited evidence for buprenorphine, although theoretical reasons why it may be a good choice for
these patients. Hydromorphone and oxycodone cannot be recommended because of extremely
Fliss E. M. Murtagh, MRCGP, MSc, is Research Training Fellow, Department of Palliative Care & Policy, Kings
College, London; Mee-Onn Chai, MSc, MRPharmS, is Pharmacist, Kings College Hospital, London; Polly M.
Edmonds, FRCP, is Consultant in Palliative Medicine, Kings College Hospital, London; Paul Donohoe, MRCP,
PhD, Consultant Nephrologist, Kings College Hospital, London; Irene J. Higginson, PhD, FFPHM, FRCP, is Professor of Palliative Care, Department of Palliative Care & Policy, Kings College, London.
Address correspondence to: Dr. Fliss E. M. Murtagh, Department of Palliative Care and Policy, Weston Education Centre, Cutcombe Road, London, SE5 9RG, UK (E-mail:fliss1@doctors.org.uk).
Journal of Pain & Palliative Care Pharmacotherapy, Vol. 21(2) 2007
Available online at http://jppcp.haworthpress.com
2007 by The Haworth Press, Inc. All rights reserved.
doi:10.1300/J354v21n02_03

JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

limited evidence, although each is likely a better choice than morphine or diamorphine. Morphine
and diamorphine themselves are not recommended because of known accumulation of potentially
toxic metabolites. doi:10.1300/J354v21n02_03 [Article copies available for a fee from The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail address: <docdelivery@haworthpress.com> Website:
<http://www.HaworthPress.com> 2007 by The Haworth Press, Inc. All rights reserved.]

KEYWORDS. Opioid analgesics, kidney failure, pain, practice guidelines, pharmacology

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INTRODUCTION
The numbers of patients with non-cancer diagnoses cared for by palliative care services remains low. In 2003, less than 7% of patients
within specialist palliative care services across
England, Wales & Northern Ireland had diagnoses other than cancer,1 although this conceals
wide local variation.1,2 There have been calls to
extend specialist palliative care services to conditions other than cancer on the basis of equity
and need,3,4 although debate continues about
how far this provision should extend, which aspects of specialist palliative care are most effectively transferable, and the potential challenges
involved.5 In the United States, a small but
growing number of hospice programs now report that the majority of their patients have diagnoses other than cancer.
End-stage renal disease (ESRD) is defined
by the National Kidney Foundation as the most
advanced stage of renal dysfunction (stage 5),
when the estimated glomerular filtration rate
(eGFR) is less than 15 mL per minute.6 It is important to calculate eGFR and not rely on serum
creatinine alone because the former is a much
more accurate reflection of renal function, and
the two do not correlate well. As the issue of palliative care for patients with diseases other than
cancer has developed, ESRD has had relatively
little attention, but the profile of palliative care
in relation to ESRD is now rising, because:
The dialysis population is increasing by 10%
per annum across developed countries.7,8 This
increase is not uniform, but includes disproportionate numbers of those who are elderly, dependent and suffering multiple co-morbidities.9 The rising number of elderly and ill patients with ESRD is related to changing demographics,10 with aging populations (the incidence of renal failure is strongly age-related 11)
and substantial increase in prevalence of Type 2
diabetes mellitus.7

There is increasing recognition among

nephrologists that dialysing those with increasing dependency and multiple co-morbidities
may not improve their survival, and may adversely affect their quality of life.12,13 Increasing numbers are therefore being managed conservatively (without dialysis). In the UK, about
15 to 20% of patients reaching ESRD may currently be recommended for management without dialysis.12
Palliative and supportive care of the patient
with ESRD is gaining a higher profile within
the renal field.14,15 There is growing recognition within nephrology of the importance of
training in end-of-life care,16,17 and in the UK
the recent Renal National Standards Framework includes palliative recommendations.18
So although the absolute numbers of ESRD
patients seen within palliative care services remains low, individual services are increasingly
seeing patients in whom ESRD is the primary
diagnosis, and this trend is set to continue.
These patients may be in one of two groups:
Patients who are conservatively managed,
without dialysis
Patients who withdraw from dialysis
The former group is growing, for the reasons
described above. Work by Smith and colleagues suggests that the median survival of
these patients is about six months from the putative dialysis date.12 Those withdrawing from
dialysis have a median survival of about eight
days from stopping dialysis.19 Management of
both these groups of patients can be challenging, principally because of the constraints on
the use of medications by reason of the renal
failure, but also because of the very high levels
of co-morbidity.
This paper is intended therefore to provide a
resource to those managing pain in ESRD pa-

Murtagh et al.

tients managed without dialysis, and those who

have withdrawn from it. (Analgesic use in patients on dialysis raises different considerations
and will not be addressed here; readers are referred to the review by Dean for an overview of
opioid use in dialysis patients.20) This paper
also applies to those patients with advanced
malignancy or other pathology who develop
progressive renal failure towards the end of life.

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GENERAL PRINCIPLES
Careful attention must be given to the underlying cause of the pain, as for any other palliative care patient. There is little evidence on the
prevalence of pain in conservatively managed
ESRD patients, but what evidence there is suggests that physical causes of pain are more
likely to be due to co-morbid conditions than
the renal disease itself, with ischemic pain from
peripheral vascular disease, neuropathic pain
from polyneuropathy (often related to diabetes
mellitus), bony pain from osteoporosis, or
musculoskeletal pains from a variety of causes.21
There may be specific pains related to the renal
disease, such as bone pain from renal osteodystrophy, cyst pain in polycystic kidney disease, or the infrequent but severe pain of
calciphylaxis,22,23 but pains specific to the renal
disease are less common.
Many of the common causes of pain in renal
patients are long term, and this may influence
both patient attitudes to the pain, and the professionals approach to identifying and addressing
it. There is evidence that severe chronic pain in
these patients is common and often underrecognized and undertreated.21 Adjuvant analgesics
and non-pharmacological methods of pain control are important to consider, but since some of
the major challenges in pain management arise
in the use of opioids in ESRD patients, this paper focuses on opioid analgesia in particular.
Opioid analgesics are here categorised according to the steps of the World Health Organization analgesic ladder.24 This is a tool (see Figure
1) devised and evaluated by the World Health
Organisation to promote effective pain relief in
cancer,25 and more recently adapted for use
with patients with renal insufficiency.26,27 It
recommends that, if pain occurs, there should

FIGURE 1. WHOs Pain Relief Ladder

Freedom from
Cancer Pain

Opioid for mod

severe pain, erate to
Non-opioid
Adjuvant
Pain persi
st
increasin ing or
g
Opioid for
mild to mo
derate pain
Non-opio
id
Adjuvan
t
Pain pe
rs
increas isting or
ing

Non-op
io
Adjuv id
ant

be prompt oral administration of drugs in the

following sequence:
Step 1: non-opioids, such as acetaminophen (paracetamol)
Step 2, if the patient is still in pain, use of
mild opioid analgesics
Step 3, if pain persists, substitution (and
titration) of strong opioid analgesics such
as morphine in place of the Step 2 opioid,
until the patient is free of pain
To maintain freedom from pain, drugs
should be given by the clock, that is every 3-6
hours, rather than on demand. This three-step
approach of administering the right drug in the
right dose at the right time is inexpensive and
has been shown to be 80-90% effective for cancer patients.25 Recent evaluation in ESRD,
demonstrates that it leads to effective treatment
of pain in > 90% of haemodialysis patients.27
The Table 1 summarizes the recommendations
for practice following these steps, for ESRD
patients who are not receiving dialysis.
STEP ONE ANALGESIC MEDICATION
Acetaminophen (Paracetamol)
Step one of the ladder recommends the use of
non-opioid medication. This paper focuses pre-

JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

TABLE 1. Summary of Recommendations for Opioid Use in ESRD (eGFR < 15 mL/minute) Without Dialysis
World Health
Organization Analgesic
Ladder Categories
Step 1

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Step 2

Analgesic

In ESRD Managed Without

Dialysis eGFR
< 15 mL/minute

Acetaminophen
(paracetamol)

Recommended

Codeine

Not recommended

Comments
Maximum 3 g per 24 hours orally
when eGFR < 10 mL per minute

Dihydrocodeine

Not recommended

Dextropropoxyphene

Avoid

Hydrocodone

Not recommended

Tramadol

Use with caution

50 mg 12 every 12 hours orally

Morphine

Not recommended (see text

re: short-term use)

Subcutaneous starting dose: 2.5

mg every 4-12 hours as required

Diamorphine

Not recommended; see text

re: short-term use

Subcutaneous starting dose: 2.5

mg every 4-12 hours as required

Buprenorphine

Limited evidence

Use with caution (reduce dose

and increase interval)

Fentanyl

Recommended

Consider reducing dose by

25-50%; Starting dose for
subcutaneous use: 25 micrograms
Q4H as required

Alfentanil

Recommended but not for

as required use

Use in CSCI only, when volume

makes higher doses of fentanyl
impractical

Hydromorphone

Limited evidence

Use with caution. Starting dose:

1.3 mg every 8 hours orally

Methadone

Recommended, with specialist Reduce dose by 50-75%. Wide

advice on prescribing
inter-individual variations.

Oxycodone

Limited evidence

Step 3

dominantly on opioids, however, for completeness it should be stated that acetaminophen is

the non-opioid analgesic of choice in ESRD
patients. Some authorities recommend an increase in the dose interval from every six to
every eight hours when eGFR < 10 mL per minute.28
STEP TWO ANALGESIC MEDICATION
Codeine/Dihydrocodeine
Codeine is metabolized in the liver to a variety
of metabolites (norcodeine, codeine-6-glucuronide, morphine, normorphine, morphine-3-glucuronide, and morphine-6-glucuronide).29 The
majority of these metabolites are pharmacologically active (although the degree of activity is
unclear) and excreted renally, and their renal

Use with caution. Starting dose:

2.5 mg every 8-12 hours orally

clearance is greatly reduced in advanced renal

disease.30 There are also reports of serious side
effects following codeine use in patients with
advanced renal failure, in particular severe
hypotension,31 respiratory arrest,32 and profound narcolepsy.33 Dihydrocodeine has similar metabolism and elimination to codeine, and
there are reports of prolonged narcosis.34,35
Both codeine and dihydrocodeine should
therefore be avoided whenever possible. It is
sometimes not practicable to avoid them altogether, in which case considerable caution
should be used, and the dose reduced to 25 to
50% of normal.28 Accumulations of active metabolites will occur on repeated dosing with risk
of adverse effects as described above. Review
and careful monitoring for hypotension, excessive sedation or respiratory depression is
needed. Constipation is also to be expected, and

Murtagh et al.

should be anticipated with appropriate laxative

prescribing.

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Dextropropoxyphene (Propoxyphene)
Dextropropoxyphene is primarily metabolized in the liver to norpropoxyphene, which is
then excreted renally. Norpropoxyphene accumulates in renal insufficiency,36,37 and it is
thought to be toxic (causing both sedation and
respiratory depression),28 largely on the basis
of animal studies.38 Both dextropropoxyphene
and norpropoxyphene contribute to its cardiac
toxicity, with the potentially fatal complication
of depressing cardiac conduction.39 For these
reasons, it is not recommended for use in
ESRD. Dextropropoxyphene has been withdrawn in some countries as a single agent product due to high reported incidences of adverse
drug reactions.
Hydrocodone
Hydrocodone is semi-synthetic congener of
codeine. It has similar actions to codeine, but is
more potent or a weight for weight basis, and is
widely used in the US and Canada, where it is
frequently used in combination with acetaminophen but not available in the UK and some
other European counties. It is metabolized predominantly by O-demethylation, and N-demethylation, to hydromorphone and norhydrocodone, respectively,40 and is excreted renally,
both as the parent compound and as the metabolites, with considerable interindividual variation.40 The metabolites appear to have analgesic activity equal or greater than that of the
parent compound, but there is little data on the
activity of norhydrocodone, and no data on the
pharmacokinetics of hydrocodone or its metabolites in renal impairment, other than that described in the section on hydromorphone (see
below). In view of its similarity to codeine, and
the lack of data in renal impairment, its use cannot be recommended.
Tramadol
Tramadol is a peripherally and centrally acting analgesic that acts both on opioid receptors and by inhibiting monoamine (norepinephrine and serotonin) reuptake.41 It is metabolized

in the liver with just one pharmacologically active metabolite, O-demethyl-tramadol, and
90% of the oral dose is excreted via the kidneys.42 In severe renal impairment, there is
about a two-fold increase in the elimination
half-life (this original data included ten patients
with renal impairment, with creatinine clearances ranging from 5 to 80 mL per minute).42 It
is therefore recommended that the dose interval
should be increased from every four to six hours
to every twelve hours, and a lower dose be given
(50 mg rather than 100 mg).43 For the same reason, the modified release preparation is best
avoided. It is also important to remember that
uremia lowers the seizure threshold; tramadol
may be epileptogenic in ESRD patients and
should therefore be used with caution in those
patients with a very high urea, as well as those
with risk of seizures for other reasons or who
may be taking other medication which lowers
seizure threshold, such as selective serotonin
re-uptake inhibitors (SSRIs).44
In practice, tramadol, with both dosage and
interval modifications, is useful in providing
pain relief to ESRD patients not on dialysis who
cannot tolerate stronger opioid analgesics.
Clinical experience indicates that ESRD patients may have a higher incidence of drowsiness, confusion and lethargy on tramadol, especially with repeated administration, but it is the
Step 2 opioid analgesic which is least problematic for this population. Close observations and
asking patient to self-report adverse effects
early is useful in achieving a partnership to
manage pain without compromising safety.
STEP 3 ANALGESIC MEDICATION
Morphine and Diamorphine
Morphine is metabolized in the liver to
normorphine,morphine-3-glucuronide(M-3-G),
and morphine-6-glucuronide (M-6-G), and, in
patients with normal renal function, these are
excreted renally, together with about 10% unchanged morphine.45 In patients with renal
failure, these metabolites accumulate significantly.46-49 The pharmacological activity and
clinical significance of M-6-G and M-3-G have
been much discussed. To summarize, M-6-G
has some analgesic activity, the extent of which

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10

JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

is unclear (it may be more potent than morphine

itself but results are conflicting).50,51 More crucially, it is known to depress the central nervous
system.52 It appears to cross the blood brain barrier slowly, and once it is within the brain, its action may be prolonged.49,53 M-3-G is less well
understood; it appears to have no analgesic activity,54 but is neurotoxic in animals,55 and
may possibly antagonise the analgesic effects
of morphine and M-6-G.56 The extent of this
antagonist effect is unclear and there have
been contradictory findings in different studies.57-59
Diamorphine is simply di-acetylated morphine (heroin), a legitimate opioid available in
the UK and several other countries. Once
within body tissues, it is rapidly de-acetylated
to morphine, and 6-monoacetyl-morphine, and
subsequently behaves as morphine, described
above.
With the increasing availability of alternative strong opioids, such as fentanyl and
alfentanil, morphine and diamorphine are no
longer first choice for use in ESRD patients
who are not dialysed, because of the problems
with metabolite accumulation, and because at
least some of these metabolites are clinically
significant. If morphine or diamorphine are
used in the last few days of life, there is increased risk of terminal agitation caused by
accumulation of these active metabolites.60
Morphine and diamorphine should therefore
perhaps only be used in the short term for acute
uncontrolled pain (i.e., needing an injectable
opioid) and when alternative opioids are not
easily available. Because of the rapid accumulation in ESRD, the change to an alternative
opioid should be made within one or two days,
and preferably within hours. There are certain
clinical situations, such as an out-of-hours home
visit because of unexpected deterioration, when
this situation arises: alternative opioids, particularly alternative injectable opioids, may not be
readily available in the community. Efforts
should be made to anticipate and to avoid these
situations, but it reasonable to use morphine
or diamorphine, for example over a weekend,
rather than leave a patient without effective analgesia. The following general recommendations should be followed:

Use small doses of morphine or diamorphine. A recommended subcutaneous

starting dose would be morphine 5 mg or
diamorphine 2.5 mg in an opioid-nave
patient (or even less in a frail elderly patient).
Titrate carefully according to response. This
will necessitateregular and frequent review, especially in the first day. As required doses to
control pain may be required much less frequently than in a patient with normal renal function because of rapid accumulation. If there is a
need for ongoing analgesia in a continuous subcutaneous infusion (CSCI), then morphine or
diamorphine is not the opioid of choice.
Myoclonus may be due to accumulation of
morphine/diamorphine and their metabolites
as well as to uremia: careful assessment for
other opioid side effects are vital to distinguish
the two. It is also important to remember that
morphine or diamorphine will be cleared very
slowly, if at all, and any adverse central nervous
system effects will be both delayed in onset and
prolonged in action.49
Buprenorphine
Buprenorphine is a potent partial -opioid
receptor agonist, -opioid receptor antagonist
and a weak -opioid receptor agonist. Buprenorphine is metabolised in the liver to norbuprenorphine, and buprenorphine-3-glucuronide (B3-G).61 These metabolites are excreted via the
kidney, while unchanged buprenorphine is excreted principally via the biliary system.61,62
There has been the little evaluation in renal failure. One study of five ESRD patients showed
no change in the pharmacokinetics after a single parenteral dose of buprenorphine, as compared to healthy volunteers,63 although only
buprenorphine levels were measured. Hand
and colleagues showed that metabolite (but not
parent drug) levels during buprenorphine infusion were significantly higher in patients with
renal impairment (creatinine clearances < 9 mL
per minute) compared to healthy controls:
norbuprenorphine rose four-fold, and B-3-G
rose fifteen-fold, but with wide variation between individuals.61 Norbuprenorhine is 40
times less potent analgesically than buprenor-

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Murtagh et al.

phine, while B-3-G is analgesically inactive.61

It is not clear, however, whether these metabolites cause adverse effects. Both studies in humans reported no adverse effects, but one study
in rats has demonstrated B-3-G is a more potent
respiratory depressant than buprenorphine,64
while a further study in rats demonstrated that
high dose buprenorphine alone had very limited effect on arterial blood gases, although
high dose buprenorphine and midazolam together depressed respiration significantly.65
Buprenorphine has the advantage of being
available in sublingual, transdermal, and injectable preparations in the UK and some other
countries; in the US, it is only available for analgesia in parenteral form. It is worth noting that
buprenorphine is omitted from some reviews of
opioids in renal impairment,20,66 partly because
of limited availability in some countries. The
lack of evidence about use of buprenorphine in
renal impairment in humans means that it cannot be recommended unequivocally, but there
are theoretical reasons suggesting it may be relatively safe. In view of the limited evidence, it
should be used with caution; dose reduction, increased dose interval and careful monitoring is
advisable, at least until more evidence is
available and definitive recommendations can
be made.
Fentanyl and Alfentanil
Fentanyl is a potent and highly lipid-soluble
synthetic opioid. It is metabolizedin the liver by
N-dealkylation and hydroxylation, to norfentanyl and other metabolites that are all inactive
and non-toxic.38,67 Less than 10% is excreted
unchanged in the urine.
In renal failure, no dose modification appears to be necessary when fentanyl is given as
a bolus injection,68 but there is limited evidence
on the pharmacokinetics when it is administered either in repeated doses or by continuous
infusion. In addition, most data on use of
fentanyl in renal impairment relate to intravenous administration. There is considerable
interpatient variability in fentanyl pharmacokinetics. Prolonged sedation was observed in
critically ill patients given fentanyl as a continuous infusion and the half-life of fentanyl increased to 25 hours.38 Studies have also reported

11

that the parent compound may accumulate with

sustained administration.69
Despite these concerns about accumulation,
fentanyl is, on present limited evidence, the
preferred opioid, simply because the metabolites are known to be inactive and non-toxic. Its
main disadvantage is that it is only currently
available for chronic pain management in
transdermal or injectable forms (trans-mucosal
fentanyl is suitable for breakthrough or incident
pain only, rather than control of ongoing
chronic pain). Some authorities have suggested
dose reduction with declining renal function:
75% of normal dose if creatinine clearance is 10
to 50 mL per minute, and 50% normal dose if
creatinine clearance is < 10 mL per minute.28
Although this may be an overly cautious approach, it could prevent the accumulation of a
drug which exhibits considerable inter-patient
variation. Careful monitoring for any gradual
development of accumulation and toxicity
would certainly be wise in any case of repeated
administrations and there may be some basis
for gradual dose reduction if fentanyl is used
over days or weeks. The very wide individual
variation in its pharmacokinetics67,70 would
support this cautious approach.
As in patients with normal renal function,
fentanyl transdermal patch is best introduced in
ESRD patients when pain is already controlled
by an alternative route of analgesia. Because of
the length of time taken to change dose, it is not
appropriate for uncontrolled pain. There have
also been anecdotal reports of respiratory depression following use of the fentanyl 25 g per
hour patch,71 particularly in opioid-nave patients started on a fentanyl patch without previous opioid exposure, although a lower strength
fentanyl patch (12 g per hour) is now available
which will reduce this risk.
When used subcutaneously, a starting dose
of fentanyl 25 g as required is appropriate, titrating according to response, and converting to
CSCI if needed regularly. Doses of 150 to 250
g per twenty-four hours by CSCI are often sufficient to control pain well.
Alfentanil is shorter-acting than fentanyl,
and is both less potent and less lipid soluble. It is
also metabolised by the liver, mostly by N- and
O-dealkylation, to inactive metabolites, which
are renally cleared.72 The analgesic potency of
alfentanil is one-quarter that of fentanyl, with

12

JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

an onset of action four times more rapid than

equianalgesic dose of fentanyl.73 In clinical
practice, its only additional advantage over
fentanyl is a smaller volume of injection when
used in CSCI, useful especially when higher
doses are needed. It is not ideal for as required
parenteral use because of its short duration of
action; fentanyl is preferable.

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Hydromorphone
Hydromorphone is an analogue of morphine, but with a shorter duration of action. It is
metabolized in the liver and its main metabolite, hydromorphone-3-glucuronide (H-3-G) is
excreted renally, and accumulates in renal impairment.20,74,75 The activity of H-3-G in humans has not been fully established. It is known
to be neuro-excitatoryin rats 76 and these effects
have also been reported in humans.77 Myoclonus and mental status changes have also
been reported in patients with acute renal failure given high doses of hydromorphone.78
A single-dose study indicates hydromorphone accumulation in renal impairment 74
(with proportionately greater accumulation in
more severe renal impairment), and a further
detailed pharmacokinetic case study over 14
days demonstrated clear accumulation of
H-3-G.75 There has therefore been some concern about the use of hydromorphone. However, a retrospective review by Lee and colleagues suggests that hydromorphone may be
better tolerated than morphine in patients with
renal impairment.79 This study included 29 patients with renal impairment of a range of severity, 80% of whom had an improved side effect
profile after switching from morphine to
hydromorphone. However, the retrospective
nature of the study make it hard to draw firm
conclusions, and the mean urea and creatinine
levels reported suggest the majority of these
study patients had only mild renal impairment.
Overall, the evidence to support the safety of
hydromorphone in renal impairment is extremely limited. Certainly dose reduction and
careful titration is important. Farrell and Rich
suggest an alternative dosing schedule of 1.3
mg every eight hours.80

Methadone
Methadone is a synthetic opioid with mixed
properties. It is a basic and lipophilic drug with
high volume of distribution. Methadone is metabolised primarily by the liver to several metabolites. Most of the main metabolite, 1.5dimethyl-2-ethyl-3,3-diphenyl-1-pyrroline, is
excreted in the faeces, although renal excretion
of the unchanged drug is also an important route
of methadone elimination.
Methadone displays large pharmacodynamic and pharmacokinetic interindividual variations and considerable difference between
acute and chronic phase dosing, with accumulation of methadone on repeated administration
in tissues due to its high volume of distribution.
There is evidence, from a study of two patients
with chronic renal failure on maintenance
methadone, that plasma concentrations are no
higher than in those with normal renal function,81 suggesting that fecal excretion might
compensate in those with renal impairment.
Because of this, and the limited possibilities for
use of other opioids, methadone has been used
clinically for patients with renal failure,
particularly for neuropathic pain.
Caution should be exercised on two counts
however: firstly, because there is well-described risk of accumulation and toxicity with
methadone (in patients with normal renal function), experienced specialist supervision of
methadone use should be available, and secondly, because of the wide individual variation,
doses and effects should be closely monitored.
The titration and use of methadone is fully described elsewhere,82,83 but in severe renal impairment a dose reduction of 50 to 75% is recommended.28,38
Oxycodone
Oxycodone is metabolised in the liver, principally to noroxycodone, but also to oxymorphone. Both of these compounds are active metabolites. Less than 10% is excreted unchanged
in urine.84 Several studies have shown low levels of oxymorphone in patients with normal renal function, leading to the conclusion that it
probably does not contribute much by way of
pharmacological activity.85-87 However, this
cannot be assumed in patients with renal im-

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Murtagh et al.

pairment. A pharmacokinetic study by Kirvela

and colleagues of ten uremic patients showed
that the elimination of oxycodone in renal failure is significantly prolonged, and excretion of
its metabolites is severely impaired,84 with
wide interindividual variation. Work by Kalso
and colleagues also suggest some of the effects
of oxycodone may be mediated through its metabolites.88
This leads to the conclusion that there are
question marks about the use of oxycodone in
renal impairment, and insufficient evidence to
determine whether or not it is safe for use in this
population. Because of the limited alternative
oral opioids available for use in renal impairment, some clinicians use it with caution, while
others avoid using it. There is one anecdotal report of central nervous system toxicity and sedation with oxycodone in renal failure.89
Broadbent et al. suggest the use of 75% of normal dose when creatinine clearance is 10-50
mL per minute, and 50% when creatinine clearance < 10 mL per minute (with unchanged dose
intervals).28 Again, this approach is not so
much based on evidence, as cautious in the
knowledge of the very limited evidence available.
CONCLUSIONS
The numbers of ESRD patients managed
without dialysis that are currently seen by specialist palliative care services are small, but
managing these patients symptoms well can
prove extremely challenging. Pain is common,
and has probably been substantially under-recognized and under-treated in the past. There is
an acute need for evidence-based recommendations for practice, as awareness grows within
both palliative and renal fields of the need for
active, anticipatory symptom control, as well
as other palliative and supportive care provision for these patients. This review provides a
summary of the available evidence, and recommendations for practice based on the limited
evidence.
There is urgent need for further research in
this area. Studies of patients with renal impairment often amount to a few participants for
each analgesic. Hopefully this will change as
the profile of symptom control in ESRD rises,

13

and awareness grows of the need for such work,

despite the difficulties it raises. Meanwhile, a
detailed understanding of analgesic pharmacology in renal impairment, use of this understanding to inform practice, and collaborative
working between nephrologists, palliative care
teams, pharmacists, and primary care teams,
are the key to optimum care of these patients.
REFERENCES
1. National Council for Hospices and Specialist
Palliative Care. BriefingAugust 2004. Minimum Data
Sets Project. 2004. National Council for Hospices and
Specialist Palliative Care.
2. Edmonds P. Kings College Hospital Palliative
Care Team Annual Report 2003-4. 2004. London, Kings
College Hospital.
3. Standing Medical Advisory Committee and Standing Nursing and Midwifery Advisory Committee. The
Principles and Practice of Palliative Care. 1992. London, Standing Medical Advisory Committee and Standing Nursing and Midwifery Advisory Committee.
4. NHS Executive. EL(96)85. A Policy Framework
for Commissioning Cancer Services: Palliative Care
Services. 1996. London, NHS Executive.
5. Field D, Addington-Hall J. Extending specialist
palliative care to all? Soc Sci Med 1999; 48(9):1271-80.
6. National Kidney Foundation. K/DOQI clinical
practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Amer J of Kidney
Dis 2002; 39(2 (Suppl 1)):S1-S266.
7. Ansell D, Feest T, editors. UK Renal Registry
Report 2003. Renal Registry, Bristol, UK. 2004.
8. United States Renal Data System 2001 Annual
Data Report. 2001. Bethesda, MD, USA.
9. Roderick PJ, Ferris G, Feest TG. The provision
of renal replacement therapy for adults in England and
Wales: recent trends and future directions. QJM 1998;
91(8):581-7.
10. Seale C. Changing patterns of death and dying.
Soc Sci Med 2000; 51(6):917-30.
11. Feest TG, Mistry CD, Grimes DS, Mallick NP.
Incidence of advanced chronic renal failure and the need
for end stage renal replacement treatment. BMJ 1990;
301(6757):897-900.
12. Smith C, Silva-Gane M, Chandna S, Warwicker
P, Greenwood R, Farrington K. Choosing not to dialyse:
evaluation of planned non-dialytic management in a cohort of patients with end-stage renal failure. Nephron
Clinical Practice 2003; 95(2):c40-6.
13. Munshi SK, Vijayakumar N, Taub NA, Bhullar
H, Lo TC, Warwick G. Outcome of renal replacement
therapy in the very elderly. Nephrol Dial Transplant
2001; 16(1):128-33.
14. Chambers EJ, Germain M, Brown E. Supportive
Care for the Renal Patient. 1st ed. Oxford University
Press, 2004.

Downloaded By: [Canadian Research Knowledge Network] At: 04:42 27 April 2009

14

JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

15. Levy JB, Chambers EJ, Brown EA. Supportive

care for the renal patient. Nephrol Dial Transplant 2004;
19(6):1357-60.
16. Cohen LM, Reiter GS, Poppel DM, Germain MJ.
Renal palliative care. In: Addington-Hall J, Higginson I,
editors. Palliative Care for Non-Cancer Patients. Oxford: Oxford University Press, 2001:103-23.
17. Holley JL, Carmody SS, Moss AH, Sullivan AM,
Cohen LM, Block SD et al. The need for end-of-life care
training in nephrology: national survey results of nephrology fellows. Am J Kidney Dis 2003; 42(4):813-20.
18. Department of Health. National Service Framework for Renal ServicesPart 2. 2005. Department of
Health, London.
19. Catalano C, Goodship THJ, Graham KA, Marino
C, Brown AL, Tapson JS et al. Withdrawal of renal replacement therapy in Newcastle upon Tyne: 1964-1993.
Nephrology Dialysis Transplantation 1996; 11(1):133-9.
20. Dean M. Opioids in renal failure and dialysis patients. Journal of Pain & Symptom Management 2004;
28(5):497-504.
21. Davison SN. Pain in hemodialysis patients: prevalence, cause, severity, and management. American Journal of Kidney Diseases 2003; 42(6):1239-47.
22. Angelis M, Wong LL, Myers SA, Wong LM.
Calciphylaxis in patients on hemodialysis: a prevalence
study. Surgery 1997; 122(6):1083-9.
23. Rich A, Leach A, Ellershaw J. A case of difficult
pain in a patient with chronic renal failure and calciphylaxis. Journal of Pain and Symptom Management, 2001;
22: 1; 617-21.
24. World Health Organisation. Cancer pain relief.
World Health Organisation, editor. 1986. Geneva, World
Health Organisation.
25. http://www.who.int/cancer/palliative/painladder/
en/. Internet communication, accessed 22.9.2006
26. Launay-Vacher V, Karie S, Fau JB et al. Treatment of pain in patients with renal insufficiency: the
World Health Organization three-step ladder adapted. J
of Pain 2005; 6(3):137-48
27. Barakzoy AS, Moss AH. Efficacy of the World
Health Organization analgesic ladder to treat pain in
end-stage renal disease. JASN Express. Published on
September 20, 2006 as doi: 10.1681/ASN.2006050477
28. Broadbent A, Khor K, Heaney A. Palliation and
chronic renal failure: opioid and other palliative medicationsDosage guidelines. Progress in Palliative Care,
2003, 11; 4:183-90
29. Vree TB, Verwey-van Wissen CP. Pharmacokinetics and metabolism of codeine in humans. Biopharm
Drug Dispos 1992; 13(6):445-60.
30. Guay DR, Awni WM, Findlay JW, Halstenson
CE, Abraham PA, Opsahl JA et al. Pharmacokinetics
and pharmacodynamics of codeine in end-stage renal
disease. Clin Pharmacol Ther 1988; 43(1):63-71.
31. Parke TJ, Nandi PR, Bird KJ, Jewkes DA. Profound hypotension following intravenous codeine phosphate. Three case reports and some recommendations.
Anaesthesia 1992; 47(10):852-4.

32. Talbott GA, Lynn AM, Levy FH, Zelikovic I.

Respiratory arrest precipitated by codeine in a child with
chronic renal failure. Clin Pediatr (Phila) 1997; 36(3):
171-3.
33. Matzke GR, Chan GL, Abraham PA. Codeine
dosage in renal failure. Clin Pharm 1986; 5(1):15-6.
34. Redfern N. Dihydrocodeine overdose treated with
naloxone infusion. Br Med J 1983; 287(6394):751-2.
35. Barnes JN, Goodwin FJ. Dihydrocodeine narcosis in renal failure. Br Med J 1983; 286(6363):438-9.
36. Wolen RL, Ziege EA, Gruber CM, Jr. Determination of propoxyphene and norpropoxyphene by chemical ionization mass fragmentography. Clin Pharmacol
Ther 1975;17(1):15-20.
37. Gibson TP, Giacomini KM, Briggs WA. Propoxyphene and norpropoxyphene plasma concentrations in
the anephric patient. Clin PharmacolTherap 1980, 27; 5:
665-70.
38. Davies G, Kingswood C, Street M. Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacokinet 1996; 31(6):410-22.
39. Nickander R, Smits SE, Steinberg MI. Propoxyphene and norpropoxyphene: pharmacologic and toxic
effects in animals. J Pharmacol Exp Ther 1977; 200(1):
245- 53.
40. Cone EJ, Darwin WD, Gorodetzky CW, Tan T.
Comparative metabolism of hydrocodone in man, rat,
guinea pig, rabbit and dog. Drug Metabolism and Disposition 1978;6(4):488-93.
41. Dayer P, Collart L, Desmeules J. The pharmacology of tramadol. Drugs 1994; 47(Suppl 1):3-7.
42. Lee CR, McTavish D, Sorkin EM. Tramadol. A
preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute
and chronic pain states. Drugs 1993; 46(2):313-40.
43. Ashley C, Currie A. The Renal Drug Handbook.
Second edition ed. Abingdon, UK: Radcliffe Medical
Press Ltd, 2004.
44. Gardner JS, Blough D, Drinkard CR, Shatin D,
Anderson G, Graham D et al. Tramadol and seizures:
a surveillance study in a managed care population.
Pharmacother 2000; 20(12):1423-31.
45. Hasselstrom J, Sawe J. Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active
opioid concentrations. Clin Pharmacokinet 1993; 24(4):
344-54.
46. Sawe J, Odar-Cederlof I. Kinetics of morphine in
patients with renal failure. Eur J Clin Pharmacol 1987;
32(4):377-82.
47. Aitkenhead AR, Vater M, Achola K, Cooper
CM, Smith G. Pharmacokinetics of single-dose I.V.
morphine in normal volunteers and patients with endstage renal failure. Br J Anaesth 1984; 56(8):813-9.
48. Wolff J, Bigler D, Christensen CB, Rasmussen
SN, Andersen HB, Tonnesen KH. Influence of renal
function on the elimination of morphine and morphine
glucuronides. Eur J Clin Pharmacol 1988; 34(4):353-7.

Downloaded By: [Canadian Research Knowledge Network] At: 04:42 27 April 2009

Murtagh et al.

49. Bodd E, Jacobsen D, Lund E, Ripel A, Morland J,

Wiik-Larsen E. Morphine-6-glucuronide might mediate
the prolonged opioid effect of morphine in acute renal
failure. Hum Exp Toxicol 1990; 9(5):317-21.
50. Hanna MH, DCosta F, Peat SJ, Fung C, Venkat
N, Zilkha TR et al. Morphine-6-glucuronide disposition
in renal impairment. Br J Anaesth 1993; 70(5):511-4.
51. Osborne R, Joel S, Slevin M. Morphine intoxication in renal failure; the role of morphine-6-glucuronide.
Br Med J (Clin Res Ed) 1986; 293(6554):1101.
52. Andersen G, Christrup L, Sjogren P. Relationships among morphine metabolism, pain and side effects
during long-term treatment: an update. J Pain Symptom
Manage 2003; 25(1):74-91.
53. Angst MS, Buhrer M, Lotsch J. Insidious intoxication after morphine treatment in renal failure: delayed
onset of morphine-6-glucuronide action. Anesthesiology 2000; 92(5):1473-6.
54. Mercadante S. The role of morphine glucuronides in cancer pain. Palliat Med 1999; 13(2):95-104.
55. Shohami E, Evron S, Weinstock M, Soffer D,
Carmon A. A new animal model for action myoclonus.
Adv Neurol 1986; 43:545-52.
56. Smith MT, Watt JA, Cramond T. Morphine-3glucuronidea potent antagonist of morphine analgesia.
Life Sci 1990; 47(6):579-85.
57. Hewett K, Dickenson AH, McQuay HJ. Lack of
effect of morphine-3-glucuronide on the spinal antinociceptive actions of morphine in the rat: an electrophysiological study. Pain 1993; 53(1):59-63.
58. Gong QL, Hedner J, Bjorkman R, Hedner T.
Morphine-3-glucuronide may functionally antagonize
morphine-6-glucuronide induced antinociception and
ventilatory depression in the rat. Pain 1992; 48(2):249-55.
59. Suzuki N, Kalso E, Rosenberg PH. Intrathecal
morphine-3-glucuronide does not antagonize spinal antinociception by morphine or morphine-6-glucuronide in
rats. Eur J Pharmacol 1993; 249(2):247-50.
60. Kirkham SR, Pugh R. Opioid analgesia in uraemic
patients. Lancet 1995; 345(8958):1185.
61. Hand CW, Sear JW, Uppington J, Ball MJ, McQuay
HJ, Moore RA. Buprenorphine disposition in patients
with renal impairment: single and continuous dosing,
with special reference to metabolites. Br J Anaesth 1990;
64(3):276-82.
62. Mercadante S, Arcuri E. Opioids and renal function. J Pain 2004; 5(1):2-19.
63. Summerfield RJ, Allen MC, Moore RA, Sear
JW, McQuay HJ. Buprenorphine in end stage renal failure. Anaesthesia 1985; 40(9):914.
64. Ohtani M, Kotaki H, Nishitateno K, Sawada Y,
Iga T. Kinetics of respiratory depression in rats induced
by buprenorphine and its metabolite, norbuprenorphine.
J Pharmacol Exp Ther 1997; 281(1):428-33.
65. Gueye PN, Borron SW, Risede P, Monier C,
Buneaux F, Debray M et al. Buprenorphine and midazolam act in combination to depress respiration in rats.
Toxicol Sci 2002; 65(1):107-14.

15

66. Robson P. The use of opioids in palliative care

patients with renal failure. CME Cancer Medicine 2004,
2; 2: 40-8
67. Labroo RB, Paine MF, Thummel KE, Kharasch
ED. Fentanyl metabolism by human hepatic and intestinal
cytochrome P450 3A4: implications for interindividual
variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 1997; 25(9):1072-80.
68. Coral IM, Moore AR, Strunin L. Plasma concentrations of fentanyl in normal surgical patients with severe renal failure. Br J Anaesth 1980; 52:101.
69. Koehntop DE, Rodman JH. Fentanyl pharmacokinetics in patients undergoing renal transplantation.
Pharmacotherapy 1997; 17(4):746-52.
70. Bentley JB, Borel JD, Nenad RE, Jr., Gillespie
TJ. Age and fentanyl pharmacokinetics. Anesth Analg
1982; 61(12):968-71.
71 palliativedrugs.com 2003. Internet communication, accessed 12.5.2005
72. Meuldermans W, Van Peer A, Hendrickx J,
Woestenborghs R, Lauwers W, Heykants J et al.
Alfentanil pharmacokinetics and metabolism in humans. Anesthesiology 1988; 69(4):527-34.
73. Scholz J, Steinfath M, Schulz M. Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil. An update. Clin Pharmacokinet 1996; 31(4):275-92.
74. Durnin C, Hind ID, Wickens MM, Yates DB,
Molz KH. Pharmacokinetics of oral immediate-release
hydromorphone (Dilaudid IR) in subjects with renal impairment. Proc West Pharmacol Soc 2001; 44:81-2.
75. Babul N, Darke AC, Hagen N. Hydromorphone
metabolite accumulation in renal failure. J Pain Symptom Manage 1995; 10(3):184-6.
76. Wright AW, Mather LE, Smith MT. Hydromorphone-3-glucuronide: a more potent neuro-excitant
than its structural analogue, morphine-3-glucuronide.
Life Sci 2001; 69(4):409-20.
77. Fainsinger R, Schoeller T, Boiskin M, Bruera E.
Palliative care round: cognitive failure and coma after
renal failure in a patient receiving captopril and hydromorphone. J Palliat Care 1993; 9(1):53-5.
78. Kurella M, Bennett WM, Chertow GM. Analgesia in patients with ESRD: A review of available evidence. Amer J Kidney Dis 2003, 42; (2): 217-28.
79. Lee MA, Leng ME, Tiernan EJ. Retrospective
study of the use of hydromorphone in palliative care patients with normal and abnormal urea and creatinine.
Palliat Med 2001; 15(1):26-34.
80. Farrell A, Rich A. Analgesic use in patients with
renal failure. European Journal of Palliative Care 2000;
7(6):201-5.
81. Kreek MJ, Schecter AJ, Gutjahr CL, Hecht M.
Methadone use in patients with chronic renal disease.
Drug Alcohol Depend 1980; 5(3):197-205.
82. Morley JS, Makin MK. The use of methadone in
cancer pain poorly responsive to other opioids. Pain Reviews 1998; 5:51-8.

16

JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

Downloaded By: [Canadian Research Knowledge Network] At: 04:42 27 April 2009

83. Blackburn D, Somerville E, Squire J. Methadone: an alternative conversion regime. Europ J Palliat
Care 2002; 9(3):93-6.
84. Kirvela M, Lindgren L, Seppala T, Olkkola KT.
The pharmacokinetics of oxycodone in uremic patients
undergoing renal transplantation. J Clin Anesth 1996;
8(1):13-8.
85. Kaiko RF, Benziger DP, Fitzmartin RD, Burke
BE, Reder RF, Goldenheim PD. Pharmacokineticpharmacodynamic relationships of controlled-release
oxycodone. Clin Pharmacol Ther 1996; 59(1):52-61.
86. Poyhia R, Vainio A, Kalso E. A review of oxycodones clinical pharmacokinetics and pharmacodynamics.
J Pain Symptom Manage 1993; 8(2):63-7.
87. Heiskanen T, Olkkola KT, Kalso E. Effects of
blocking CYP2D6 on the pharmacokinetics and pharma-

codynamics of oxycodone. Clin Pharmacol Ther 1998;

64(6):603-11.
88. Kalso E, Vainio A, Mattila MJ, Rosenberg PH,
Seppala T. Morphine and oxycodone in the management of cancer pain: plasma levels determined by chemical and radioreceptor assays. Pharmacol Toxicol 1990;
67(4):322-8.
89. Fitzgerald J. Narcotic analgesics in renal failure.
Conn Med 1991; 55(12):701-4.

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ACCEPTED: 10/20/06

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