Understanding the Toxicology of Diazepam
Because of its widespread use as an anxiolytic, muscle relaxant, preoperative sedative, and seizure medication, diazepam (Valium) is one of the most commonly encountered drugs on urine toxicology reports. The metabolism and excretion of diazepam is somewhat convoluted; however, with a basic understanding of the excretion toxicology, providers will be able to easily identify patterns of recent diazepam use and distinguish these from patterns of noncompliant benzodiazepine use.
Diazepam toxicology is often the cause of much confusion in the field of compliance monitoring. This is largely due to the fact that patients who are prescribed or using diazepam will not actually test positive for the parent drug but rather for one, or a combination of, its three metabolites. The three metabolites of diazepam—nordiazepam, temazepam, and oxazepam—are quickly recognized as individual benzodiazepines, which can be prescribed for a variety of medical conditions. It is imperative that providers be able to identify patterns of recent diazepam use and distinguish these from patterns of separate nordiazepam, temazepam, and oxazepam use so that patients are not accused of using nonprescribed medications.
Following administration, diazepam is extensively metabolized via oxidative pathways into three pharmacologically active metabolites. The primary urinary metabolite, nordiazepam (desmethyldiazepam), undergoes subsequent metabolic transformation into oxazepam. Temazepam, another active metabolite of diazepam, also undergoes further metabolic transformation into oxazepam. Figure 1 details the metabolic pathways of diazepam into nordiazepam, temazepam, and oxazepam.
Figure 1. Metabolic transformation pathways of diazepam into nordiazepam, temazepam, and oxazepam.
As seen in Figure 1, oxazepam is the final metabolic product of the two primary metabolites and therefore can be thought of as the end product of diazepam metabolism (similar to the role of morphine in heroin metabolism). Frequent or daily users of diazepam will commonly test positive for all three metabolites, which represents and should be recognized as the “textbook” toxicology pattern of recent diazepam use (see Figure 2).
Figure 2. Toxicology report showing recent use of diazepam.
Urine toxicology reports of daily or frequent diazepam users will most likely indicate the presence of all three metabolites and therefore allow for easy identification of the textbook diazepam pattern. However, the urine of infrequent or recreational users often produces slightly different patterns that providers also must be able to recognize. The most commonly encountered of these patterns is shown in Figure 3.
Figure 3. Toxicology report showing trace levels of oxazepam, a metabolite of diazepam, which indicates semi-recent use of the latter agent.
As the end product of diazepam metabolism, oxazepam often is present at slightly higher concentrations in the urine than nordiazepam and temazepam. Thus, oxazepam often remains detectable in the urine for a day or two after the other metabolites have been fully eliminated. If patients are drug tested several days after their last dose of diazepam, it is not uncommon to detect only trace levels (<300 ng/mL) of oxazepam. Although the presence of only oxazepam is quite different from the textbook diazepam pattern discussed above, it must be recognized as a pattern of semi-recent diazepam use because of the large number of patients who use this medication on a prescribed-as-needed (PRN) basis. If low urinary concentrations of oxazepam are not recognized as a possible pattern of diazepam use, patients may be incorrectly accused of using oxazepam (Serax).
Although the presence of nordiazepam, temazepam, and oxazepam in the urine of a patient may be explained by the use of three individual benzodiazepines, it also should be recognized as the textbook pattern of recent diazepam use. Patients using diazepam on an infrequent or PRN basis may not exhibit the textbook pattern because of the different excretion profiles of the individual metabolites.