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What symptoms are associated
with high plasma morphine levels?
Breastfed infants may be exposed
through breast milk to active
metabolites of codeine, such as
morphine. High plasma morphine levels
can cause central nervous system (CNS)
depression, signs of which include
missing feeds, poor weight gain,
poor latching, hypotonia, difficulty
breathing and prolonged sleep.
These may occur in as many as 24%
of infants whose mothers are taking
codeine.6,8–10 Signs of CNS depression
in babies of mothers using codeine
typically manifest after approximately
four days of breastfeeding, due to
signs and symptoms associated with
high plasma morphine levels include
severe constipation, sleepiness,
impaired breathing and confusion.
Both mothers and infants should be
monitored for signs and symptoms of
high morphine levels.
Why do these symptoms develop?
Various non-genetic factors can
influence the responses of both the
mother and the infant to drugs.
For example, maternal dose and length
of treatment influence codeine toxicity,
as well as prematurity, infant age and
weight, concurrent disease states,
renal or liver function6,15
influencing exposure such as amount
of milk ingested.
parameters do not fully explain toxicity,
and genotype also appears relevant.
One important source of variations
in drug metabolism arises from
genetic variations in cytochrome P450
enzymes such as CYP2D6, which is
particularly relevant to codeine, and
can cause substantial variation in drug
efficacy and toxicity.
codeine is converted to morphine
by CYP2D6-mediated metabolism
(see Figure 1).
Approximately 5–10% of a dose of
the pro-drug codeine undergoes
hepatic CYP2D6-mediated conversion
to morphine. Subsequent morphine
metabolism involves phase II
metabolism glucuronidation by
UDP-glucuronosyltransferase (UGT) 2B7
into morphine-3-glucuronide (inactive)
and morphine-6 -glucuronide (active).
Approximately 80% of a codeine dose
is converted to inactive metabolites.
This involves CYP3A4 conversion
into norcodeine and conversion by
into codeine-6 -glucuronide.
Because multiple enzymes are involved,
various genes can affect this process.
Individuals can differ considerably
in CYP2D6 metabolic rates, with
a spectrum of poor, intermediate,
extensive and ultra-rapid metabolisers.2
The proportion of each type can differ
considerably between populations12
but based on European figures, as many
as 10% or more Australians may have
gene variants resulting in deficiency,
or even complete lack of CYP2D6 activity
can have diminished, sometimes
virtually absent, conversion of codeine
to morphine, greatly reducing analgesic
This may contribute to some
cases of high codeine use. However, this
article will focus on genetic variants
leading to potential toxicity due to
higher levels of conversion of codeine
For example, some individuals possess
multiple copies of the CYP2D6 gene,
with increased CYP2D6 enzyme levels,
resulting in ultra-rapid metabolism.
Based on European populations,
between 3–10% or more Australians
may be ultra-rapid metabolisers
but prevalence can be up to 30%
or more in people of Northeastern
African or Arabian backgrounds.
New genotyping technologies21 provide
more accurate individual assessments
than those based on ethnicity alone.22
Ultra-rapid metabolisers are at higher
risk of adverse effects such as opioid
toxicity due to increased rates of
conversion of the pro-drug codeine
to morphine. For example, it has
been reported that following a single
oral codeine dose of 30 mg, CYP2D6
ultra-rapid metabolisers have at least
1.5-fold higher exposure to morphine
than other individuals.
Codeine may be used for analgesia
following a C-section or episiotomy.
There are several case reports of serious
complications potentially related to
codeine toxicity, including apnoea and
7,15,19,23 In one reported
death of a 13-day-old infant, genetic
testing showed the mother was a
CYP2D6 ultra-rapid metaboliser, which
the authors concluded had resulted in
elevated breast milk morphine levels
and fatal morphine accumulation in the
Importantly, the mother also had
another relevant genetic factor
The UGT2B7 enzyme
is involved in phase II metabolism,
Figure 1. Codeine metabolism
Morphine -3 -glucuronide
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