Higher postmortem pregabalin concentrations in a heroin-use subgroup were a statistical finding, not a direct measurement of higher doses or a universal fatal concentration. A two-year study found different concentration distributions, but the authors cautioned that the magnitude did not establish substantially greater pregabalin toxicity in that subgroup.
The study tested an entire submitted-blood cohort
Nahar and colleagues studied 3,750 coronial cases with femoral-vein blood from deceased people aged at least 16 years. The methods and results specify January 2016 through December 2017; the abstract instead ends the period in December 2016. The two-year period stated in the methods is the basis for describing the cohort here.
Pregabalin was detected in 229 cases: 69 classified as heroin users and 160 as non-heroin users. The latter category did not establish lifelong abstinence from heroin. Classification depended on recent toxicology findings and supporting circumstances.
Screening included a quantitative method
Pregabalin and a deuterated internal standard were extracted from 100 µL of femoral-vein blood by acetonitrile protein precipitation and analyzed using LC–MS/MS. The reported linear range was 0.5–50.0 µg/mL, and a concentration of at least 0.5 µg/mL counted as positive. Positive samples were quantified in duplicate.
The observed case range extended above that stated calibration range. The population paper does not set out the dilution procedure for every high result, so the range should not be described as evidence of an undiluted assay validated to 540 µg/mL. Nor did the study provide a uniform postmortem interval or specimen-storage history for reconstructing individual concentration changes.
Which comparison produced which result?
Across all 229 positive cases, pregabalin ranged from 1 to 540 µg/mL. Among heroin users, the range was 1–540 µg/mL and the median 8.0 µg/mL; among non-heroin users, the range was 1–168 µg/mL and the median 5.5 µg/mL. The full-group Mann–Whitney comparison gave p = 0.012.
Investigators then removed two suspected intentional-overdose cases from the heroin group and eleven from the comparison group, using scene and case information. The remaining 67 and 149 cases had medians of 8 and 5 µg/mL, respectively, and the comparison gave p = 0.002. The 75th percentiles were 16 and 11 µg/mL. The smaller p value describes that restricted analysis, rather than the original 69-versus-160 comparison.
Why concentration was not a recovered dose
The authors interpreted the findings as compatible with greater pregabalin consumption among heroin users. They also identified an alternative explanation: different intervals between ingestion and death could produce different concentrations even without a proportional dose difference. Those intervals generally were unknown.
This was observational postmortem casework, not a controlled administration study. Prescription histories and doses were generally unavailable, preventing confident separation of prescribed treatment from illicit misuse. The paper discussed limited redistribution based on earlier literature; it did not measure each decedent’s antemortem-to-postmortem change.
What the result contributes to a death investigation
A measured concentration can support evaluation of exposure alongside other drugs, scene evidence and pathology. It cannot independently establish the dose, timing, impairment or cause of death. Comparison with therapeutic plasma ranges also requires caution because this study measured postmortem whole blood.
The significant distribution difference and the authors’ caution about clinical importance must travel together. For another example of why group comparisons cannot correct an individual result, see postmortem versus antemortem fentanyl comparisons.
Primary source
Nahar LK, Murphy K, Paterson S. Toxicological Relevance of Pregabalin in Heroin Users: A Two-Year Postmortem Population Study. Journal of Analytical Toxicology. 2022;46:471–478. doi:10.1093/jat/bkab070.
Leave a Reply