THE BENZODIAZEPINES: HOW DANGEROUS ARE THEY?

The classification of drugs in the benzodiazepine category are chemical agents that suppress central nervous system activity. They are very commonly prescribed in the treatment of disorders of anxiety, sleep regulation, and seizures. They are also utilized as muscle relaxants and as anesthesia induction agents (Ciraulo & Sarid-Segal, 2004). Another class of drugs-the nonbenzodiazepine hypnotics-is also described in this column. Both the benzodiazepine and the non-benzodiazepine drugs have abuse liability and produce a withdrawal syndrome upon abrupt discontinuation after chronic use.

The benzodiazepines quickly replaced the more dangerous barbiturates because they were less toxic in overdose, had fewer drug-drug interactions, and had a much better efficacy (Greenblatt & Shader, 1974). In fact, the benzodiazepines are one of the most commonly prescribed categories of medications, with alprazolam at the top of the list. Prevalence for the nonmedical use of these medications has been reported to be in excess of 2% for adults in the United States with about 10% of these individuals meeting the criteria for sedative-hypnotic use disorder (Becker, Sullivan, Tetrault, Desai, & Fiellin, 2008). In addition, there is a trend of increasing numbers of individuals visiting emergency rooms with problems related to benzodiazepine misuse with rates exceeded only by the misuse of opioids (Jones, Mogali, & Comer, 2012). In drug-related suicide attempts, the benzodiazepines comprise the second most frequently involved drug (with the opioids being the first; Substance Abuse and Mental Health Services Administration, 2011). Kan, Hilberink, and Breteler (2004) identified that the odds for developing a substance use disorder increases with longer duration of treatment with benzodiazepines or the administration of higher doses. Other factors found to correlate to the development of benzodiazepine dependence, especially in older adults, include being female, the presence of cognitive impairment, panic disorder, or suicidal ideation (Voyer, Preville, Roussel, Berbiche, & Beland, 2009). In 2013, over 7,000 people died of an overdose involving benzodiazepines (Centers for Disease Control and Prevention, 2015). Individuals with a history of alcohol use disorders comprise one group who has a high rate of benzodiazepine-use-related problems, and about 20% of alcoholic patients presenting for treatment may be abusing benzodiazepines (Johansson, Berglund, Hanson, Pohlen, & Persson, 2003). Another group with problematic benzodiazepine use are those with a history of opioid use disorder including those receiving opioid maintenance treatment (Jones et al., 2012). Chen et al. (2011) report that 47% of patients in a methadone maintenance program have a history of benzodiazepine use, with more than half having started using benzodiazepines after entering the methadone program. In addition, the use of benzodiazepines is also high for patients in buprenorphine maintenance programs (Lavie, Fatseas, Denis, & Auriacombe, 2009).

Most of the benzodiazepines are metabolized by the liver through the cytochrome P450 enzyme system, with many benzodiazepines being substrates to the CYP3A4 enzyme. This has implications when patients are also taking other medications that act as either inducers or inhibitors of the CYP3A4 enzyme. Several of the benzodiazepines have active metabolites, and as a result, those medications are cleared from the body very slowly. Commonly used benzodiazepines with active metabolites include temazepam (Restoril) and diazepam (Valium). Both have the active metabolite oxazepam (Serax). There are also a few benzodiazepines that are metabolized through the alternate route of glucuronidation. Those medications (lorazepam [Ativan] and oxazepam) do not rely on the hepatic enzyme system to metabolize them and therefore are safer in patients with impairments of hepatic function.

Abuse potential of the benzodiazepines is a complex process, and it is believed that the onset of action and lipophilicity are the main correlates leading to addictive processes in the brain. Thus, those benzodiazepines with rapid onset and rapid brain uptake seem to be the most addictive. Nevertheless, all the benzodiazepines have been found to be potentially addictive. It should be noted that the use of benzodiazepines purely for their euphoric effect is rare unless they are used in combination with other drugs of abuse, which results in a "boost" effect. Many authorities have reported that the Z-drugs (zolpidem, zopiclone, eszopiclone, and zaleplon) have a lower potential for abuse than the traditional benzodiazepines. However, there are multiple reports of abuse after prolonged use of these agents (Ciraulo & Knapp, 2014). In research studies that assess abuse potential, the Z-drugs have been found to produce euphoric effects at doses above their typical therapeutic ranges. However, postmarketing monitoring has shown a relatively low potential for abuse for zolpidem considering how often it is prescribed (Greenblatt et al., 2000).

Although benzodiazepines have been found to have an improved safety profile over the barbiturates, they are nevertheless associated with acute and chronic risks. For instance, misuse (and even using as prescribed) can cause sedation, psychomotor impairment, and memory problems, which affect attention and concentration. It has been well established that benzodiazepine use produces anterograde amnesia and difficulty acquiring new learning (Stewart, 2005). Although tolerance usually develops to most of the cognitive effects, this is not universal. In addition, when benzodiazepines are used intermittently (i.e., on a "PRN" basis), tolerance may not develop, and the patient will continue to be at risk for psychomotor impairments and memory problems-especially in the first few hours after taking the drug. The good news is that, even in patients with persistent cognitive impairment, when the benzodiazepines are stopped, substantial improvement is noted-although the patients do not return to their prebenzodiazepine sensorium (Barker, Greenwood, Jackson, & Crowe, 2004).

The benzodiazepines are considered as a widely used and abused class of medications. Patients diagnosed with anxiety disorders have been found to be at a lower risk to abuse the medication. However, patients with comorbid alcohol use disorder and those in methadone maintenance programs are at a very high risk of misuse of benzodiazepines-both prescribed and not prescribed. The Z-drugs mentioned above, although found to have a lower risk of misuse, have a potential for addiction risk. The prudent clinician will properly manage the patient prescribed with benzodiazepines by monitoring the use, therapeutic effects, and side effects and randomly utilizing urine drug screens. Changes in sensorium and observation of other inappropriate behaviors as identified above should always be further explored and evaluated.

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