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Opiate toxicity in patients with renal failure

BMJ 2006; 332 doi: (Published 09 February 2006) Cite this as: BMJ 2006;332:345

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Pain Management in Renal Failure - Choice of opioid

Editor – Conway has highlighted the difficulties in managing painful
conditions in patients with renal failure (1). However, the suggestion
that opioids should be avoided in this group of patients may encourage
undertreatment of pain in individuals with renal failure. Patients with
chronic kidney disease frequently report pain (2) and patients with
cancer often develop severe renal impairment (3).

Whilst patients on opioids should be monitored for adverse effects,
particular opioids are likely to cause toxicity in renal patients. These
include morphine, diamorphine and codeine derivatives which produce toxic
metabolites which accumulate in renal failure. Studies report profound
respiratory depression and narcosis when renal patients are given these
opioids (4)(5).
We agree with the suggestion that opioids which accumulate in renal
failure should be avoided. However, suggesting buprenorphine for mild to
moderate pain and alfentanil for severe pain requires further discussion.

Buprenorphine is metabolised in the liver to norbuprenorphine and
buprenorphine-3-glucoronide. The parent drug is excreted unchanged via the
billiary system but the metabolites are excreted by the kidneys. Although
the metabolites have little analgesic action in humans, they do accumulate
in renal failure (6). B-3-G is a potent respiratory depressant in rats and
its action in humans as yet, is unclear (7). Buprenorphine has not been
adequately studied in humans with renal failure and therefore it cannot be
recommended as first choice for mild to moderate pain in renal failure.
We have successfully used immediate-release tramadol on an 8-12hrly basis
in renal patients. Tramadol is metabolised in the liver to one active
metabolite, O-demethyl-tramadol and 90% of the parent drug and its
metabolites are excreted by the kidneys. In comparison with codeine,
tramadol causes less adverse effects and does not cause significant
respiratory depression for a given level of analgesia (8). Although
limited, the evidence for the cautious use of tramadol in renal patients
is greater than it is for buprenorphine (9). Thus, immediate-release
tramadol would be our first choice analgesic for patients with renal
failure with mild to moderate pain.

Conway suggests alfentanil for severe pain in renal failure.
Alfentanil is metabolised in the liver to non-toxic metabolites which are
renally excreted. Only 1% of the parent drug is excreted unchanged by the
kidneys. However, it can only be given parentally. This is not
convenient for the majority of people with chronic painful conditions and
renal failure, who are not in the terminal phase of their illness.
In general, the evidence for the safe use of opioids in patients with
renal failure and severe pain is limited. However, the literature
suggests that both Hydromorphone and Oxycodone are safer than morphine or
diamorphine and our clinical experience supports this. Furthermore, they
can be given in the oral form and are more suitable for managing chronic
painful conditions.
Hydromorphone is metabolised in the liver to Hydromorphone-3-Glucoronide,
which is excreted in the urine and accumulates in renal failure. None the
less, patients with renal impairment in a palliative care unit had an
improved side-effect profile when switched from morphine to Hydromorphone

Oxycodone is metabolised in the liver, principally to noroxycodone
and also to oxymorphone. 10% of the parent drug is excreted unchanged by
the kidneys. Although the metabolites are excreted in the urine and
studies show that accumulation occurs in renal failure, there have been
few adverse effects reported (11). In our experience, when creatinine
clearance <10ml/minute, pain can be managed effectively using 50% of
the normal dose, as suggested by Broadbent (12).

The evidence does not support the use of codeine, morphine, pethidine
or diamorphine for people with renal failure and severe pain. Given the
evidence from the literature and our own clinical experience, we would
recommend tramadol for mild to moderate pain. For those renal patients
with severe pain, alfentanil is recommended if the parental route is
appropriate and hydromorphone or oxycodone where the oral route is


1. Conway BR, Fogarty DG, Nelson WE, Doherty CC. Opiate toxicity in
patients with renal failure. BMJ 2006;332:345-346.

2. Davison SN. Pain in Hemodialysis Patients: Prevalence, Cause,
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3. Humphreys BD, Soiffer RJ & Magee CC. Renal failure associated
with cancer and its treatment: An update. J Am Soc Nephrol 2005:16;151-

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6. 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 Aneasth

7. 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):428-433

8. Desmeules JA. The Tramadol option. Eur J Pain 2000;4(suppl.A):15-

9. Izzedine H, Launay-Vacher V, Abbara C, Aymard G et al.
Pharmacokinetics of Tramadol in a Hemodialysis Patient. Nephron

10. Lee MA, Leng ME, Tiernan EJ. Retrospective study of the use of
Hydromorphone in palliative care patients with normal and abnormal urea
and creatinie. Palliative Med 2001;15(1):26-34

11. Kirvela M, Lindgreen L, Seppala T, Olkkola KT. The
Pharmacokinetics of Oxycodone in Uremic Patients Undergoing Renal
Transplantation. J of Clin Anaesth 1996;8:18-18

12. Broadbent A, Khor K, Heaney A. Palliation and chronic renal
failure: Opioid and other palliative medications – Dosage guidelines.
Progress in Palliative Care 2003;11(4):183-190

Competing interests:
None declared

Competing interests: No competing interests

04 March 2006
Claire A Douglas
SpR Palliative Medicine
Alistair F Douglas
Arrowe Park Hospital, Wirral, CH49 5PE