Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens

Archives of Pathology & Laboratory Medicine, Apr 1997 by A A Piergies, S Sainati, B Roth-Schechter

Objective.-To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott AD^sub x^ urine drug screens assays.

Design.-Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg).

Setting.-Clinical Pharmacology Unit within a teaching hospital.

Main Outcome Measures.-Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADX urine drug assay system, each performed at two different laboratory assay sites.

Results.-Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva

EMIT II or the Abbott AD^sub x^ urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests.

Conclusions.-These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

(Arch Pathol Lab Med 1997;121:392-394)

Urine screening assays for drugs of potential abuse and for illicit drugs have become ubiquitous and are commonly used either as part of preemployment evaluation or as spot checks for safety and other purposes during the term of employment. The underlying mechanisms of drug reactivity and identification most often used in urine drug screens are immunologic, including those employed in the Syva EMIT II test (Syva Company, San Jose, Calif) and the Abbott Diagnostics AD^sub x^ test (Abbott Laboratories, Diagnostic Division, Dallas, Tex).1 Although most urine drug screens are specific and highly sensitive, it has been reported that false-positive results can be obtained from drugs that are not included in the screening tests.2,3 It is hypothesized that such drugs and/or their metabolites may cross-react and bind nonspecifically to the antibodies in the test kits.3

Ambien (zolpidem) is a widely prescribed nonbenzodiazepine hypnotic.4 It is effective in the treatment of various types of insomnia in adults, including the elderly.5-8 Zolpidem is characterized by a rapid onset of action and a short half-life of 2.5 hours with production of at least four major metabolites, none of them pharmacologically active.9 Restoril (temazepam) is an intermediate-acting benzodiazepine hypnotic that is similarly indicated for the treatment of insomnia.10,11 Temazepam has an elimination half-life of approximately 8.8 hours and is completely metabolized through conjugation prior to excretion.11

As an imidazopyridine, the chemical structure of zolpidem is different from the benzodiazepines and all other drugs of potential abuse.12 Since its introduction in 1992, no evidence of its abuse has emerged. Nevertheless, inasmuch as zolpidem interacts primarily with only one of the central benzodiazepine binding sites,13 and because benzodiazepines are routinely screened for as abused drugs, it could be hypothesized that zolpidem interacts with antibodies directed at benzodiazepines in criterion standard urine drug screens. Therefore, the present study was designed to test for cross-reactivity of zolpidem and/ or its metabolites in the Syva EMIT II and Abbott AD^sub x^ urine drug screen tests. At the time the study was initiated, according to the market surveillance data available, temazepam was the most commonly prescribed hypnotic benzodiazepine.l4 Consequently, it was tested in the same systems as the positive control.

METHODS

Subjects and Procedures

After approval by the Institutional Review Board and informed consent from subjects, men and women aged 18 to 40 years were enrolled in the study. Screening involved a physical examination, medical history, and clinical laboratory evaluation. Any significant medical or psychiatric disorder, pregnancy or risk of becoming pregnant, lactation, weight varying more than 15% from desirable weight based on the Metropolitan Life Insurance table (1983), or a history of exaggerated drug response excluded subjects from participation. A recent history of drug addiction, alcoholism or drug abuse, smoking, and an inability to abstain from alcohol during the study also precluded participation. Benzodiazepines had to be discontinued for at least 30 days, and the use of any over-the-counter or prescription medications within 7 days of the beginning of the study was prohibited. Finally, a positive urine drug screen for the presence of members of the following drug classes precluded study participation: benzodiazepines, amphetamines, cannabinoids, barbiturates, opiates, cocaine, and alcohol. Twenty subjects were enrolled in the study. One subject was withdrawn for having tested positively for cocaine, and 19 subjects completed the study.