Pharmacogenetics of Analgesics: Toward the Individualization of Prescription

Abstract

The 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 factors that can sometimes 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 a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the micro-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

“…Patients with the CYP2C9*2 and CYP2C9*3 alleles have lower mean daily warfarin doses and a greater risk of bleeding (113). CYP2C9 polymorphisms can also be associated with an increased rate of NSAID-induced adverse events (114). NSAIDs have been shown to effectively prevent colorectal neoplasia.…”

Naloxone‐responsive acute dystonia and parkinsonism following general anaesthesia

“…Moreover, higher cerebrospinal fluid morphine concentrations have been noted in homozygote 3435TT. Data about fentanyl are contradictory but some authors mention fentanyl as a P-gp substrate [19]. The P-gp genotypisation of this patient showed that she was indeed heterozygous for the two tested mutations (C3435:C ⁄ T and G2677T ⁄ A:G ⁄ T).…”

Role of PhaseIMetabolism in Drug Activation and Clinical Treatment Outcomes

“…10.3) is of significance in our context. First because the production of morphine (9), its active metabolite, is under strong genetic control [30]. And second, because there is a qualitative difference in the activity of drug and metabolite, in contrast with many known cases of active metabolites.…”

“…In clinical pharmacology, tramadol-induced analgesia is thus found to result from the combined and synergetic effects of four active entities. And while CYP2D6-deficient patients produce very little O-desmethyltramadol, tramadol activity is weaker but not absent in such patients [30,34].…”