Individualizing Analgesic Prescription Part I: Pharmacogenetics of Opioid Analgesics

Abstract

The current use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic processes, and each of these components, in addition to pain perception and processing, seem to be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After usual dose, drug toxicity, as well as inefficacy, can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. Thus, cytochrome P450 (CYP)2D6 polymorphism influences codeine and tramadol analgesic effects, CYP2C9 has an impact on the disposition of some nonsteroidal anti-inflammatory drugs, and opioid receptor polymorphism (118A>G) may reduce morphine potency. Moreover, drug interaction mimics genetic deficiency and contributes to the variability in response to analgesics. This two-part review summarizes the available data on the pharmacokinetic-pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes (CYP and uridine diphosphate glucuronosyltransferase), drug transporters (multidrug resistance proteins, multidrug resistance-associated proteins, organic anion-transporting polypeptides, and serotonin transporters), relevant drug targets (such as µ-opioid receptor, serotonin receptor and cyclooxygenases) and other nonopioid biological systems, on currently prescribed central and peripheral analgesics.

The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone

“…It is also now recognized that codeine and tramadol O‐demethylated metabolites are responsible for their analgesic action (Dayer et al. , 1988) The same variability would be expected with other opioids dependent on CYP pathways for their activation (Samer et al. , 2006).…”

“…Oxymorphone is moreover 14 times more potent than oxycodone (Chen et al, 1991). It is also now recognized that codeine and tramadol O-demethylated metabolites are responsible for their analgesic action (Dayer et al, 1988) The same variability would be expected with other opioids dependent on CYP pathways for their activation (Samer et al, 2006). Several pieces of indirect evidence support a role for pharmacologically active metabolites in the anti-nociceptive effect of oxycodone in both rats (Lemberg et al, 2006) and humans (Backlund et al, 1997) and a few case reports have pointed out the importance of CYP2D6 phenotype in the pharmacology of oxycodone as a result of drug interactions or genetic polymorphisms.…”

“…The activity of CYP2D6 may also influence risks for substance dependence (Tyndale et al, 1997). The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned, but whether CYP2D6 genetic polymorphism results in phenotypic differences in the antinociceptive response has not been fully investigated Heiskanen et al, 1998;Lalovic et al, 2006;Samer et al, 2006). The importance of CYP3A mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone needs further investigation.…”

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

“…Codeine is an ineffective analgesic in CYP2D6 poor metabolizers (PM) because of deficient O-demethylation of codeine to morphine (Desmeules and Dayer, 1991) whereas the genotype of ultrarapid metabolizers (UM) has been associated with higher morphine exposure and serious safety concerns (Gasche et al, 2004). The same variability would be expected with other opioids dependent on CYP pathways for their activation (Samer et al, 2006;. Several pieces of indirect evidence point to the role of pharmacologically active metabolites in the anti-nociceptive effect of oxycodone in rats (Lemberg et al, 2006a) and humans (Backlund et al, 1997).…”

Safety Issues of Pharmacological Acute Pain Treatment in Children

“…79 The risk of opioid toxicity increases with age (younger than 1 year), comorbidities, such as obesity, prematurity, obstructive sleep apnea, respiratory, hepatic, and neurological dysfunction, otolaryngologic surgery, drug-drug interactions ( Tables 2 and 3), and genetic variation in genes coding for drug-metabolizing enzymes, transporters, or targets. 73,80 Specific epidemiological studies assessing the frequency of neurological ADRs in children are lacking, but increased opioid sensitivity (including CNS effects) has been reported in young infants, in particular preterm, due to organ immaturity. In the postoperative setting, neonates and young infants seem more sensitive to central opioid ADRs (sedation and respiratory depression) than older infants and adults and require significantly lower doses of opioids.…”