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naloxone, and a high incidence of nausea (76% to 88%, depending on dose) and vomiting (60%
to 64%) (Grace & Fee, 1996 Level II).
Although it has been shown that M6G is more potent than morphine in various pain models
and that the potency ratios also vary according to route of administration (Lotsch, 2005;
van Dorp, Romberg et al, 2006), clinical studies suggest that the same amount of, or more, M6G
is required to produce the same analgesic effect as a given dose of morphine (Dahan, van Dorp
et al, 2008).
Most of the studies were not designed to look at side effects, but the incidence of nausea and
vomiting may be less than with morphine (Cann et al, 2002 Level II). In healthy volunteers,
morphine 0.15 mg/kg and M6G 0.2 mg/kg resulted in similar reductions in ventilatory
response to carbon dioxide (Romberg et al, 2003 Level III‐1).
Both M6G and M3G are dependent on the kidney for excretion. Impaired renal function, the
oral route of administration (first pass metabolism), higher doses and increased patient age
are predictors of higher M3G and M6G concentrations (Faura et al, 1998 Level IV; Klepstad et al,
2003 Level IV) with the potential risk of severe long‐lasting sedation and respiratory depression.
Genetic polymorphisms of the mu‐opioid receptor may influence the efficacy of morphine.
Several single nucleotide polymorphisms have been identified, A118G being the most
common. Patients can be genotyped as A118 homozygous (AA), that is homozygous for the
wild‐type A allele, heterozygous (AG), or homozygous for the variant G allele (GG). Studies
from Taiwan (Chou, Wang et al, 2006 Level III‐2; Chou, Yang et al, 2006 Level III‐2) and Singapore (Sia,
2008 Level III‐2) showed that patients who were GG homozygotes had increased PCA morphine CHAPTER 4
requirements in the postoperative period. However, no significant difference in morphine use
was seen in two other studies (Coulbault et al, 2006 Level III‐2; Janicki et al, 2006 Level III‐2) looking
at populations of predominantly white or mixed ethnicity patients respectively. In one of these
studies (Coulbault et al, 2006), where a trend to higher morphine requirements was associated
with the G allele, a low frequency of the G allelic variant was noted. The frequency of AG and
GG variants is higher in Asian than Caucasian populations (Landau, 2006), which could influence
results when small numbers of a mixed‐ethnicity population are studied.
Other polymorphisms at genes encoding for morphine metabolism (UGT2B7 gene) and
transport across the blood‐brain barrier by p‐glycoprotein (MDR1 gene) may also influence the
clinical efficacy of morphine (Klepstad et al, 2005). Other substrates of p‐glycoprotein, one of
the main efflux transporters, include methadone and fentanyl (Sweeney, 2007). As well as
morphine, UGT2B7 also mediates the metabolism and formation of glucuronides from other
opioids including buprenorphine, codeine, dihydrocodeine and hydromorphone, but the
clinical significance of UGT2B7 gene variants has not yet been well defined (Somogyi et al, 2007;
Holmquist, 2009).
Oxycodone
Oxycodone is a potent opioid agonist derived from the opium alkaloid thebaine. It is
metabolised in the liver primarily to noroxycodone and oxymorphone, but these metabolites
have clinically negligible analgesic effects (Lalovic et al, 2006; Riley et al, 2008). Oxymorphone, the
production of which relies on CYP2D6, is more potent than oxycodone, but plasma
concentrations are low; noroxycodone, the major metabolite and the production of which
relies on CYP3A4, is only weakly active (Coluzzi & Mattia, 2005; Lalovic et al, 2006; Holmquist, 2009).
Unlike codeine, inhibition of CYP2D6 with quinine does not reduce the analgesic effect of
oxycodone (Lalovic et al, 2006). Animal studies have shown that oxycodone is actively taken up
into the brain, resulting in a brain concentration that is up to six times those of free plasma
levels (Bostrom et al, 2008).

Acute pain management: scientific evidence 59