Pain is a frequent symptom in clinical practice. Elderly and chronically ill patients are particularly affected. On account of the high prevalence of polypharmacy among these patients, pharmacological pain therapy becomes a challenge for physicians. Drug side effects and drug-drug interactions have to be taken into account so as to minimize the health risk for these patients. Especially the group of NSAID has a high risk of adverse drug reactions and drug interactions. The gastrointestinal, the cardiovascular, the renal and the coagulation system are particularly affected. Except for the toxic effect on the liver (in a high dose) Paracetamol (acetaminophen) has similar risks, to a minor degree, though. According to current data Metamizol is actually better than its reputation. The risk of potential drug interactions seems to be low. Beside the risk of sedation in combination with other drugs, Tramadol and other opioids such as Pethidin may induce the Serotonin syndrome. In order to avoid dangerous drug interactions and adverse side effects in the case of polypharmacy, it is recommended to prefer individual choices instead of sticking to the pain management as proposed by the WHO.