Paper spray mass spectrometry for the direct, semi-quantitative measurement of fentanyl and norfentanyl in complex matrices

Background: Fentanyl is a potent, synthetic opioid at the centre of an international health crisis that has seen thousands of fatal overdoses. Most analytical methods focus on the detection of fentanyl in blood and/or urine (i.e., post-drug use). Harm reduction (including pre-screening before drug use) may be an effective strategy against fentanyl overdoses. Method: Paper spray-mass spectrometry (PS-MS) is an inexpensive, direct sampling strategy where a small volume of sample (< 10 mu L) is spotted onto a piece of paper that is then wetted and connected to high voltage. Ions are emitted from the paper and enter a mass spectrometer for sensitive and selective semi-quantitation using labeled internal standards. Results: We present the use of PS-MS for the direct measurement of fentanyl and norfentanyl using a custom PS interface, demonstrating that paper tip position and quality can significantly affect quantitative results. Furthermore, we observe comparable calibrations for fentanyl and norfentanyl (0.5 to 600 ng/mL) across a variety of complex matrices (methanol, diluted urine, analgesic slurry). Detection limits for fentanyl are as low as 0.049 ng/mL (0.4 pg total material) in methanol, and 0.66 ng/mL (5.3 pg total material) spiked in an analgesic slurry (illicit substance simulation). PS-MS was compared with liquid chromatography-MS for the analyses of real urine samples, with satisfactory results. Conclusion: PS-MS shows potential as a sensitive and selective direct measurement strategy for use in fentanyl harm reduction strategies, and may also be used for pre- screening in advance of or in combination with more conventional (i.e., chromatographic) analyses.