The opioids are metabolized by hepatic enzymes, usually to inactive glucuronide conjugates, before their elimination by the kidney. However, morphine-6-glucuronide has analgesic activity equivalent to that of morphine, and morphine-3-glucuronide (the primary metabolite) is neuroexcitatory. Codeine, oxycodone, and hydrocodone are metabolized by cytochrome CYP2D6, an isozyme exhibiting genotypic variability. In the case of codeine, this may be responsible for variability in analgesic response because the drug is demethylated by CYP2D6 to form the active metabolite, morphine. The ingestion of alcohol causes major increases in the peak serum levels of several opioids including hydromorphone and oxymorphone. Meperidine is metabolized to normeperidine, which may cause seizures at high plasma levels. Depending on the specific drug, the duration of their analgesic effects ranges from 1–2 h (eg, fentanyl) to 6–8 h (eg, buprenorphine). However, long-acting formulations of some drugs may provide analgesia for 24 h or more. The elimination half-life of opioids increases in patients with liver disease. Remifentanil, a congener of fentanyl, is metabolized by plasma and tissue esterases and has a very short half-life.