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neuropathic and inflammatory pain (Montagna, 2007). A haplotype of the GCH1 gene present in
15.4% of humans has been associated with reduced sensitivity to pain following discectomy
(Tegeder et al, 2006 Level III‐2) and homozygotes have reduced sensitivity to experimental pain
(Tegeder et al, 2008 Level III‐2).
Point mutations affecting TRPV 1 were found in a person with total insensitivity to capsaicin
(Park et al, 2007). Polymorphisms in the human TRPV 1 gene have been identified, but there has
been no systematic investigation of their functional consequences (Xu et al, 2007).
Kappa‐opioid agonists such as nalbuphine and pentazocine have greater analgesic efficacy in
women than in men (Gear et al, 1996 Level III‐3; Gear et al, 1999 Level II). Subjects carrying loss‐of‐
function melanocortin‐1 receptor gene (MC1R) variants possess a red‐hair fair‐skin phenotype
(Oertel & Lotsch, 2008). There was a significantly greater analgesic effect from a kappa‐opioid
agonist in female subjects with two variant (non‐functional) alleles of the MC1R gene
compared with those with zero or one allele (Mogil et al, 2003 Level III‐3). Subject with non‐
functional alleles also had reduced sensitivity to noxious stimuli and an increased analgesic
response to morphine‐6‐glucuronide (Mogil et al, 2005 Level III‐3). CHAPTER 1

1.6.3 Drug metabolism
Drug‐metabolising enzymes represent a major target for identifying associations between an
individual's genetic profile and drug response (pharmacogenetics) (Stamer & Stuber, 2007). The
polymorphic cytochrome P450 enzymes metabolise numerous drugs and show inter‐individual
variability in their catalytic activity. The CYP2D6 gene is highly polymorphic (Stamer & Stuber,
2007) and is of clinical interest as it influences the metabolism of codeine, dihydrocodeine,
oxycodone and tramadol to the more potent hydroxyl metabolites, which have a higher
affinity for the mu‐opioid receptor (Anderson & Palmer, 2006; Mikus & Weiss, 2005).
Over 100 allelic variants of CYP2D6 have been identified, resulting in wide variability in
function. Individuals carrying two wild type alleles display normal enzyme activity and are
known as extensive metabolisers; intermediate metabolisers are heterozygotes with two
variant alleles known to decrease enzymatic capacity; and poor metabolisers have no
functionally active alleles and have minimal or no enzyme activity (Stamer et al, 2007; Stamer &
Stuber, 2007). In Caucasian populations, 8% to 10% of people are poor metabolisers; however
3% to 5% are ultrarapid metabolisers (Stamer & Stuber, 2007).
For additional detail related to individual opioids see Section 4.1.2.
Codeine
In children and adults receiving codeine for postoperative pain, very low or undetectable
levels of plasma morphine have been noted in those with poor metaboliser or intermediate
metaboliser genotypes, but with variable impact on analgesia (Williams et al, 2002 Level II;
Poulsen et al, 1998 Level IV; Persson et al, 1995 Level IV).
CYP2D6 genotypes predicting ultrarapid metabolism (CYP2D6 gene duplication) resulted in
about 50% higher plasma concentrations of morphine and its glucuronides following oral
codeine compared with the extensive metabolisers (Kirchheiner et al, 2007 Level IV). Both the
impaired renal clearance of metabolites and genetic background (CYP2D6 ultrarapid
metaboliser status) have been implicated in reports of respiratory depression due to codeine
(Stamer & Stuber, 2007 Level IV). Morphine toxicity and death has been reported in a breastfed
neonate whose mother was an ultrarapid metaboliser of codeine (Madadi et al, 2007). CYP2D6
genotyping predicts subjects with reduced metabolism to morphine, but must be combined
with additional phenotyping to accurately predict patients at risk of morphine toxicity (Lotsch
et al, 2009 Level III‐2).

Acute pain management: scientific evidence 23