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Tramadol
O‐demethylation of tramadol by CYP2D6 produces the active metabolite
(+)‐O‐desmethyltramadol or M1, which has an affinity for mu‐opioid receptors that is
approximately 200 times more than the parent drug (Shipton, 2000). Poor metabolisers have
significantly lower plasma concentrations of M1 compared with both homozygous and
heterozygous extensive metabolisers (Stamer et al, 2003 Level III‐3; Fliegert et al, 2005 Level II) and
experience less analgesia (Poulsen et al, 1998 Level IV; Stamer et al, 2003 Level III‐3). The selective
serotonin reuptake inhibitor (SSRI) paroxetine (a CYP2D6 inhibitor) significantly inhibited (+)
and (–) tramadol metabolism by about a third (Laugesen et al, 2005 Level II). As with codeine,
impaired renal clearance of metabolites and genetic background (CYP26 ultrarapid
metaboliser status) have been implicated in cases of respiratory depression after tramadol
(Desmeules et al, 1996 Level II).
CHAPTER 1 Methadone
Genetic polymorphisms in genes coding for methadone‐metabolising enzymes, transporter
proteins (p‐glycoprotein), and mu‐opioid receptors may explain part of the observed inter‐
individual variation in the pharmacokinetics and pharmacodynamics of methadone; blood
concentrations may vary up to 20‐fold for a given dose (Li et al, 2008).
Cytochrome P450 (CYP) 2B6 and 3A4 have been identified as the main CYP isoforms involved
in methadone metabolism, but CYP2D6 has also been reported to have an effect (Li et al, 2008).
Differing effects for isomers of methadone have also been reported. Genetic variability in
CYP2B6 influenced (S)‐, and to a lesser extent, plasma (R)‐methadone concentrations;
fluoxetine (CYP2D6 inhibitor) only increased (R)‐methadone (Kharasch et al, 2004 Level III‐1); and
paroxetine (CYP2D6 inhibitor) increased steady‐state (R)‐, (S)‐, and (R, S)‐methadone in
extensive metabolisers, but only increased (S)‐methadone in poor metaboliser genotypes
(Anderson & Palmer, 2006).
NSAIDs
Wide variability in gene expression and functional polymorphisms in the COX‐2 gene (PTGS2)
may explain part of the inter‐individual variations in acute pain and the analgesic efficacy of
non‐selective NSAIDs (nsNSAIDs) and coxibs; this may be useful to predict patient risk and
benefit to drugs based on individual genetic variations (Somogyi et al, 2007; Lee et al, 2006
Level III‐2).
NsNSAIDs like ibuprofen, naproxen and piroxicam are metabolised by CYP2C9 (Rollason et al,
2008). Between 1% and 3% of Caucasians are poor metabolisers. Homozygous carriers of the
CYP2D9* 3 allele may accumulate celecoxib and ibuprofen in blood and tissues and be at risk
of increased adverse effects (Kirchheiner et al, 2003 Level III‐3; Kirchheiner et al, 2002 Level IV;
Stamer & Stuber, 2007).
Key messages
1. CYP2D6 polymorphisms affect plasma concentrations of active metabolites of codeine and
tramadol (N) (Level II).
The following tick box represents conclusions based on clinical experience and expert
opinion.
Genetic polymorphisms explain the wide inter‐individual variability in plasma
concentrations of a given dose of methadone (N).
24 Acute Pain Management: Scientific Evidence
