For pain management, opioid therapy is a mainstay for treating acute pain and relieving moderate to severe chronic pain. Quantitative measurement of opioids and their metabolites in urine is used mainly for confirmation of screened results obtained for clinical and forensic purposes. Due to limitations in interpretation of urine results for pain management testing purposes, the use of blood or serum to assess opioids and their metabolites may be of benefit. This report describes a sensitive liquid chromatography-tandem mass spectrometry method for the detection of hydrocodone and its metabolites hydromorphone, norhydrocodone, and dihydrocodeine, and other common opiates that patients may be taking, including morphine, codeine, oxycodone, and oxymorphone in a single extraction. The method uses solid-phase extraction of 500 µL of sample with quantitation by liquid chromatography-tandem mass spectrometry. The assay is linear from 1.0 to 100 ng/mL and has a between-day coefficient of variation of <10%. The major advantage of this method is that a single extraction can detect hydrocodone and its metabolites and other opiates or opioids that patients frequently use simultaneously with hydrocodone.