Demystifying Benzodiazepine Urine Drug Screen Results
Benzodiazepines, which first entered the US pharmaceutical market in the early 1960s, fall under the class of drugs referred to as sedative-hypnotics.1 Benzodiazepines possess anxiolytic, anticonvulsant, hypnotic, sedative, muscle relaxant, and amnesic effects.2 They are generally well-tolerated, safe, and effective for short-term use.
It is not uncommon for physicians to prescribe both opioids and benzodiazepines for patients with chronic pain. When used in conjunction with opioid pain medications, benzodiazepines have been shown to enhance pain relief, but the combination can be accompanied by increased risks for abuse and accidental overdose.3 According to emergency room and substance abuse treatment data (TEDS report), the combined use of benzodiazepines and opioid pain relievers is being used increasingly.4 Admissions for substance abuse treatment that reported both opioid and benzodiazepine abuse increased from 5,032 admissions in 2000 to 33,701 admissions in 2010—an increase of 569.7%. By comparison, all other admissions to treatment centers decreased by 9.6% during this same time period. In 2010, 48.2% of the benzodiazepine and opioid combination admissions reported primary opioid abuse and secondary benzodiazepine abuse, and 9.9% reported primary benzodiazepine abuse and secondary opioid abuse.4
Given the increasing and widespread use of benzodiazepines, both alone and in conjunction with other medications, it is important for clinicians to fully understand a patient’s urine drug screen (UDS) results to support the management of their care. Table 1 provides a list of generic and brand drug names, parent drug half-life information, and speed of onset for the commonly prescribed benzodiazepines.5,6
Typically, with chronic use, both parent drug and metabolite should be present in the urine upon confirmation testing using a definitive analytical methodology such as mass spectrometry. However, with prn (as needed) or recreational use, it is possible that only the parent drug or metabolite is found, depending on the time since the patient’s last dose and amount of that dose. Typical detection windows for benzodiazepines in the urine are 2 to 7 days, depending on the individual benzodiazepine drug used and other factors, such as time of last dose, drug half-life, route of administration, and individual differences in pharmacokinetics. It is beneficial to document the date of the last dose taken by the patient when submitting the sample to aid in UDS interpretations. Genetic differences in metabolic pathways resulting in fast or slow metabolism also need to be considered when evaluating UDS results.
The flow chart in Figure 1 provides parent drug and metabolites that should be encountered during benzodiazepine metabolism. Following administration, diazepam undergoes metabolism to yield the active metabolites nordiazepam and temazepam. Nordiazepam and temazepam are then further metabolized to the final active metabolic product oxazepam. Thus, the presence of nordiazepam, temazepam, and oxazepam together on a UDS is consistent with diazepam use. Since clonazepam undergoes metabolism to produce the primary urinary metabolite of 7-aminoclonazepam, the presence of this metabolite is consistent with clonazepam use. Alprazolam is metabolized after administration to the primary urinary metabolite alpha-hydroxyalprazolam. Thus, the presence of alprazolam and/or alpha-hydroxyalprazolam on a UDS would indicate recent alprazolam use. After administration, lorazepam undergoes glucuronidation to produce lorazepam-glucuronide. In a UDS, finding the parent drug lorazepam indicates recent use.6
Common limitations exist for screening benzodiazepines when using traditional immunoassay (IA) tests. IA testing for benzodiazepines often targets nordiazepam and oxazepam to measure whether an antibody-antigen response occurs, resulting in a positive or negative test result. Other benzodiazepine compounds are tested for their ability to cross react with the target drug in an IA technique. In other words, low cross-reactivity of other drugs can result in false negatives for the other benzodiazepines. The concentrations listed in Table 2 show the lowest levels that yield positive results when using the DRI Benzodiazepine Assay.7
Some commonly prescribed drugs have limited cross-reactivity. For example, lorazepam and 7-aminoclonazepam, the primary metabolite of clonazepam, have limited cross-reactivity with traditional IAs due to their molecular structures. Therefore, it is not uncommon for a laboratory to obtain a “negative” IA result for lorazepam and 7-aminoclonazepam that is indeed positive once confirmation testing with a mass spectrometer (MS) is performed. Figure 2A and 2B illustrate an example of a patient who was prescribed lorazepam and clonazepam, respectively, and the results of the testing.
Due to the probability of obtaining a false negative with the initial IA test for lorazepam and clonazepam, it is important that these compounds be tested via MS for precise drug identification. As noted, in the 2 examples, there is an explanation of the test results. Labs that specialize in this type of testing often will have comments to help the clinician interpret the results.
Benzodiazepines are widely used both as prescription medications and recreationally as agents of misuse and abuse. Because of their widespread use and availability, it is important for clinicians to evaluate benzodiazepine use in their patients. Using a UDS to help determine appropriate versus inappropriate use of these compounds will help providers offer better care to their patients. Interpretation of benzodiazepine UDS results often is not straightforward due to the complexity of the metabolic pathways of these agents, particularly diazepam, and the potential for limited cross-reactivity of the IA resulting in false negatives (lorazepam and clonazepam). Using a laboratory that understands this complexity will provide the necessary information to evaluate benzodiazepine use in your patients.