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.

Garcinia mangostana L. (GM, family Guttiferae) is one of the most widely recognized tropical fruits. GM is a wealthy pool of xanthones that exhibit a wide range of bioactivities. Tovophyllin A (TA) separated from GM pericarps was tested for its efficacy to ameliorate acetaminophen (APAP)-induced liver injury. Mice were injected with a single dose of APAP with or without TA pretreatment. The protective effects of TA against APAP-induced liver damage were evident through amelioration of serum indices of hepatotoxicity and improvement of hepatic histopathologic lesions. TA has antioxidant activity because it inhibited APAP-induced lipid peroxidation and improved the antioxidant capacity of the liver. Also, TA enhanced the mRNA expression of nuclear erythroid-related factor 2 (Nrf2) and its target genes. Protein expression of Nrf2 and heme oxygenase-1 was enhanced remarkably in TA-pretreated groups. TA suppressed activation of nuclear factor-kappa B (NF-κB) and the subsequent release of pro-inflammatory cytokines. In conclusion, TA has a marked protective activity against APAP-induced hepatotoxicity which may be linked to its ability to activate Nrf2 and inhibit the NF-κB signaling pathway.

The key role of oxidative stress in alcoholic liver disease (ALD) has been established by the large body of evidence from previous studies. Excessive consumption of ethanol induces the production of a variety of reactive oxygen species (ROS) in the liver, such as superoxide, H2O2, and hydroxyl radical. These products activate oxidant-sensitive signaling cascades and modulators of apoptosis. Because ROS accumulation is closely related to ALD, a number of studies have investigated the benefits of antioxidants. Recent studies demonstrated that polyphenol chlorogenic acid (CGA) has antioxidant properties and health benefits, such as reduction of relative risk of cardiovascular diseases and hepatoprotective effects against acetaminophen toxicity. However, the protective effects of CGA against ALD have not been studied in detail. We hypothesize that CGA plays a role in preventing ALD through its antioxidant properties. In this study, we investigated the protective effects of CGA against liver injuries in vivo. Reduced alcohol-induced-steatosis, apoptotic cell death, and fibrosis due to reduced levels of oxidative stress were observed. These findings suggest that CGA treatment can be an effective approach to attenuate ALD through the suppression of oxidative stress.

Older adults who take analgesics for chronic pain are at increased risk for adverse drug events (ADEs). The purpose of this descriptive pilot survey was to examine how older adults self-identify analgesic ADEs, and actions they take in response to analgesic ADEs. Twenty-two community dwelling older adults with chronic pain who reported an analgesic ADE associated with their chronic pain management were interviewed and asked to describe their analgesic related ADE. Written responses were content analyzed. Nineteen opioids were reported by 15, 11 NSAIDs were reported by 8, and acetaminophen was reported by 2 older adults as associated with an ADE. Gastrointestinal ADEs were most common with upset stomach (31.8%) most frequent. Neurological ADEs were also common but more varied with dizziness (27.3%) and headache (13.6%) reported most frequently. A total of 54.5% responded to their ADE by contacting their physician. Three (13.6%) went to the emergency department. A total of 36.4% stopped taking their ADE associated analgesic, 22.7% started taking a different analgesic, and 22.7% started prophylaxis. Three (13.6%) continued their ADE related analgesic. A total of 54.5% reported their symptoms subsided, but 13.6% reported their symptoms remained. A significant number of older adults with chronic pain self-manage their analgesic related ADE without contacting their primary care provider. Analgesic related ADE prevention and management should be discussed during primary care visits to reduce ADEs and enhance pain management outcomes for older adults with chronic pain.