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Cross-reactivities of some over-the-counter and uncontrolled prescription drugs with the immunoassays of some classes of drugs of abuse have been reported (1–17). Chemical structure similarity is a cause for cross-reactivity in immunoassays because the cross-reacting compound can fit onto the active sites in the antibody that has been developed for the drug of abuse or its chemical class. However, cross-reactivities from compounds that do not show explicit similarities in chemical structures with those of the target analytes are also known (1,7–10,14,15). For enzyme immunoassays, a possible explanation of some of such interferences may lie in enzyme inhibition or enzyme promotion by the interferant (18). During routine urine screening by EMIT assays (Dade Behring EMIT d.a.u. and EMIT II Plus) for drugs of abuse, we recently detected a positive benzodiazepine test that failed gas chromatographic–mass spectrometric (GC–MS) confirmation after β-glucuronidase hydrolysis and TMS derivatization. However, upon scrutinizing the GC–MS data, the analgesic drug nefopam and its metabolite desmethylnefopam were detected and characterized as the only xenobiotics in the case urine sample. Accordingly, the cross-reactivity of nefopam with the Benzodiazepine EMIT assay was tested using negative-drug urine samples spiked with nefopam in the 5 to 1000 μg/mL concentration range. This was followed by testing urine samples from volunteers who had been given two 60-mg doses of nefopam hydrochloride (Acupan® tablets) separated by a 4-h interval. The results of Benzodiazepine EMIT d.a.u. assays are given in Table I. Nefopam was found to give a positive Benzodiazepine EMIT assay at a concentration of 25 μg/mL, equivalent to the cutoff value of 200 ng/mL of oxazepam. Although nefopam urine concentrations were not quoted in the three reported overdose fatal cases (19–21), the 25 μg/mL concentration found in this study for Benzodiazepine EMIT assay cross-reactivity is not expected to result in the urine from nefopam overdose. Nevertheless, in the human body, nefopam is metabolized to desmethylnefopam, desmethylnefopam glucuronide conjugate and nefopam-N-oxide (Figure 1). Of the 87% of a dose excreted in the urine, < 5% is unchanged nefopam; metabolites constitute the rest (22). This suggests that the enhanced crossreactivity of urine from nefopam users with the Benzodiazepine EMIT assay resulted from the contribution of nefopam metabolites. Camara et al. (11) have made the same argument in explaining the cross-reactivity of oxaprozin with a Benzodiazepine immunoassay. Letter to the Editor

Cross-Reactivity of Nefopam and Its Metabolites with Benzodiazepine EMIT Immunoassay