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Introduction
Chronic pain inadequately treated is a major public health issue (1). This is particularly relevant, when we are talking of supportive care in cancer patients. Opioids are the most used analgesics for cancer pain, but the clinical benefits of opioid analgesics are dependent of substantial individual variations in the responses to opioids, insufficient drug dosing and/or a high rate of adverse events. The wide interindividual variability in sensitivity to opioids leads to unpredictable clinical responses to opioid treatment and adverse events, along with narrow therapeutic window and are still nowadays an important problem (1,2).
To date, only a limited number of studies have addressed the relationship between human genetic variations and sensitivity to opioids; however there is growing evidence that pharmacogenetic differences may impact in interindividual variability in opioid response. Human genetic variation may directly modulate opioids pharmacokinetic and pharmacodynamic effects; candidate genes are sought in polymorphisms of drug transporters, metabolizing enzymes or opioid receptors (1,2).
Cytochrome P450 (CYP) are enzymes located on the smooth endoplasmic reticulum membranes of liver hepatocytes and along the mucosal surface of the intestinal tract. The CYP system can inactivate or activate a given drug (type I reactions) and is responsible for glucuronidation and sulfation, connected with drug excretion (type II). Along with CYP iso-enzyme 3A4 (CYP3A4), the most important enzyme is CYP 2D6 (CYP2D6). She is involved in the metabolism many drugs used in pain and palliative medicine (e.g., opioids, neuroleptics, antidepressants). More than 80 distinct allelic variants for CYP2D6 are known, which leads to a wide spectrum of metabolic capacity and phenotype diversity within populations for several drugs like tramadol, dihydrocodeine, codeine (3). Fentanyl is thought to be predominantly metabolized in the liver by CYP3A4-mediated N-dealkylation (less than 1% is metabolized by alkyl hydroxylation, N-dealkylation or amide hydrolysis) (4). Ketamine is mainly metabolized by CYP2B6 and CYP3A4 (5). Morphine is metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by phase II metabolism of UDP-glucuronosyl transferase 2B7 (UGT2B7). About 60% of morphine is converted to M3G and 6–10% is converted to M6G. Both metabolites are excreted in the urine. M6G is a very potent opioid analgesic, which activates µ-opioid receptors, while M3G has no opioid properties and has been proposed to be responsible for neuroexcitatory effects, including...