QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.
1 In humans, the central analgesic effect of tramadol 100mg orally is only partially reversed by the opioid antagonist naloxone (0.8 mg intravenously). As suggested by in vitro and animal data tramadol analgesia may thus result from an action on opioid as well as monoaminergic pathways. We therefore investigated the effect of a,-adrenoceptor antagonism with yohimbine on tramadol analgesia. 2 Healthy volunteers (n = 10) received tramadol (100 mg orally), followed (+ 3 h) by yohimbine (0.1 mg kg-' intravenously), and yohimbine + naloxone (0.8 mg intravenously) and their respective placebo according to a randomized, doubleblind crossover, placebo (P) controlled design. Analgesia was assessed over 8 h by subjective pain threshold (pain intensity numerical scale-PINS) and objective pain threshold (RIII nociceptive reflex-RIII) monitoring. 3 Tramadol induced a significant increase in both pain thresholds. Peak analgesic effect was observed at 3.7 h (RIII + 39.6 f 3.9% and PINS 50.1 k s.e.mean 5%) and the analgesia lasted about 6 h. 4 Yohimbine significantly reversed the analgesic effects of tramadol for 2.8 h with a maximum decrease of 97+4% (RIII) and 67+ 12% (PINS), whereas the addition of naloxone abolished tramadol effects throughout the study period with a decrease of 90 2 6% (RIII) and 79 k 9% (PINS), P < 0.05).5 Yohimbine alone did not significantly reduce pain thresholds. 6 a,-Adrenoceptor antagonism reverses tramadol effects, thus pointing to the significant role of monoaminergic modulation and the synergy with opioid agonism in tramadol antinociception after a single oral dose.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.