The potency of these compounds result in small concentrations being detected in real-world samples, thus requiring methods utilized by a forensic or clinical laboratory to be very sensitive. Hyphenated techniques such liquid chromatography-tandem mass spectrometry (LC-MS/MS) can achieve this needed sensitivity through multiple reaction monitoring (MRM). The Shimadzu LCMS-8060 features a heated dual ionization source (DUIS) coupled with a along with ultrafast MRM acquisition software and polarity switching for increased accuracy, sensitivity and robustness. DUIS combines electrospray ionization (ESI) and atmospheric-pressure chemical ionization (APCI) by using the ESI source and the corona needle used in APCI. The development process involved MRM optimization, MS source optimization and finally column selection for a method that successfully separated and identified a mixture of synthetic opioids. This analytical method when used in combination with a validated solid phase extraction procedure, achieved sub-ng/mL detection limits in blood and urine samples.