Opiates/opioids and benzodiazepines are commonly prescribed drug therapies for acute and chronic pain. Urine drug testing is often employed to assess adherence to these mediations. Opioids and benzodiazepines are drug classes that undergo extensive metabolism through glucuronidation/sulfation. Conjugated glucuronide and sulfate drug metabolites can be difficult to detect by immunoassay and mass spectrometry methods. Consequently, false-negative or false-positive results can have a damaging impact on patient care. A common dilemma among drug-testing laboratories is whether to perform preanalytical hydrolysis to increase detection of drugs that are highly conjugated as metabolites.