Opiate toxicity in patients with renal failure

We read the article about unrecognised accumulation of opiates in
patients with renal failure as anaesthetists with interest.(1) In the
first case report a 68 yr old woman underwent a below knee amputation and
was treated with 50mg morphine plus 76mg codeine in the first 36 hours
post-operatively. We would like to comment about the choice of opioids
used.

Codeine (methyl morphine) is a pure opioid with high affinity for the
mu-receptor. Unfortunately its analgesic potency is only 10% that of
morphine and as such is less effective against severe pain than morphine.
This is due to effect that codeine needs to be metabolised to morphine by
cytochrome P-450 IID6. This enzyme exhibits genetic polymorphism and the
incidence of poor metabolisers is 7-10% in Caucasians.(2) (Morphine in
turn needs to undergo conjugation to morphine-6-glucuronide to be
clinically effective). In practice a higher percentage of the population
have noticeably limited analgesic effect possibly due to a heterozygote
impairment of metabolism.

Codeine also has a ceiling effect as an analgesic.(3) Based on the
current understanding that analgesic effect of codeine is mediated
primarily through morphine, one might anticipate that poor metabolisers
would not obtain pain relief from codeine. Experience shows this to be the
case.

Two points are worth bearing in mind. Firstly if a patient requires
morphine to control pain it is not logical to use an analgesic agent that
is a weaker prodrug, i.e. codeine at the same time. All that will be
achieved are the significant side-effects of codeine such as constipation
and respiratory depression (as reported in the article). Secondly practice
is now shifting to use step-down analgesia such as dihydrocodeine or
tramadol once pain levels drop to an appropriate level. Dihydrocodeine
does undergo metabolic conversion to dihydromorphine and dihydromoprhine-6
-O-glucuronide. However evidence exists that the parent drug rather than
its metabolites produces the analgesic effect.(4) Therefore it is a more
reliable analgesic for moderate pain than codeine. Provided dosage
regimens are restricted to 30mg (4-6 hourly) constipation is minimised.
Tramadol in turn is effective through its synergistic action on the mu-
receptor and Noradrenergic pathways. This has the least constipating
action of all drugs mentioned in this reply.

There exist case reports of prolonged narcosis associated with the
use of codeine in patients with renal insufficiency.(5) By using a drug
with limited analgesic efficacy there is a danger of overdosing the
patient in trying to achieve effective pain relief. This is when the risk
of side effects such as respiratory depression will occur in patients with
impaired renal function.

Hence the use of codeine for patients with severe pain may not be the
best choice. It is probably better to titrate pain with small doses of
morphine at frequencies indicated by degree of renal impairment and
clinical effect.

References:

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

2. Mikus G, Somogyi AA, Bochner F, Chen ZR. Polymorphic metabolism
of opioid narcotic drugs: possible clinical implications. Ann Acad Med
Singapore. 1991; 20(1): 9-12.

3. Walker DJ, Zancy JP. Subjective, psychomotor, and analgesic
effects of oral codeine and morphine in healthy volunteers.
Psychopharmacology (Berl). 1998; 140(2): 191-201.

4. Webb JA, Rostami-Hodjegan A, Abdul-Manap R, Hofmann U, Mikus G,
Kamli F. Contribution of dihydrocodeine and dihydromorphine to analgesia
following dihydrocodeine administration in man: a PK-PD modelling
analysis. Ther Drug Monit 1998; 20(5): 561-9.

5. Davies G, Kingswood C, Street M. University of Brighton, England.
Pharmacokinetics of opioids in renal dysfunction. Clinical
Pharmacokinetics. 1996; 31(6): 410-22.

Competing interests:
None declared