The use of alprazolam (Xanax®), lorazepam (Ativan®), clonazepam (Klonopin®), diazepam (Valium®), and other benzodiazepine drugs is controversial because of concerns for their safety and abuse liability (Moore, Pariente, & Begaud, 2015). These drugs are not created equal, however, and they have clinically relevant pharmacological differences. To illustrate the importance of these differences, I will review studies pertaining to the pharmacology, safety, and abuse liability of oxazepam (Serax®), a lesser known and uncommonly used benzodiazepine drug. Oxazepam was first approved in 1965 for the treatment of anxiety disorders, anxiety associated with depression, and alcohol withdrawal syndrome, and it may be used for treating insomnia. Through a review of these older and newer studies, my goal is to resurrect oxazepam from its relative obscurity and encourage readers to reconsider its use.
Pharmacology of Oxazepam
Oxazepam is a hydroxylated benzodiazepine drug that is an active metabolite of four other benzodiazepine drugs: diazepam, temazepam (Restoril®), chlordiazepoxide (Librium®), and clorazepate (Tranxene®). Oxazepam is more slowly absorbed than other benzodiazepine drugs (Buckley, Dawson, Whyte, & O'Connell, 1995), and it enters the brain more slowly than diazepam (Greenblatt & Sethy, 1990). Oxazepam is metabolized by glucuronide conjugation in the liver rather than by the cytochrome P450 system, but it does not have active metabolites and does not accumulate in the body with chronic dosing. Because of its relatively short elimination half-life (i.e., 5 to 10 hours), it is typically dosed three to four times per day. Oxazepam metabolism is not affected by age or by mild/moderate liver disease, and it is not subject to P450-mediated drug–drug interactions. Glucuronide conjugation is greater in men than women, is increased in overweight patients and cigarette smokers, and is decreased with alcohol use, in underweight or malnourished patients, and in certain disease states (e.g., hepatitis, cirrhosis, hypothyroidism, HIV infection) (Liston, Markowitz, & DeVane, 2001). These factors may therefore influence oxazepam metabolism.
The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. GABA receptor systems are the target of a wide range of drugs, including anti-anxiety, sedative-hypnotic, general anesthetic, and anticonvulsant drugs. The main GABA receptor complexes are referred to as GABA-A, GABA-B, and GABA-C, but GABA-A is the most clinically relevant. Benzodiazepine drugs bind to the GABA-A receptor complex and enhance the activity of the receptor when concomitantly bound by GABA.
The translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor, is expressed throughout the body and brain. Located on the outer membrane of mitochondria, TSPO is involved in the transport of cholesterol into mitochondria. As its former name suggests, benzodiazepine drugs may bind to the TSPO, but TSPO is pharmacologically distinct from the GABA-A receptor (Wang, Taniguchi, & Spector, 1984). As a result, not all benzodiazepine drugs bind to the TSPO. Oxazepam and diazepam bind to brain TSPO, but alprazolam does not (Schmoutz, Guerin, & Goeders, 2014). Clonazepam also has little binding affinity for TSPO compared to diazepam (Wang et al., 1984). Activation of TSPO stimulates the biosynthesis of neurosteroids from cholesterol. Neurosteroids have rapid excitatory or inhibitory effects on neuronal function (Reddy, 2010). Certain neurosteroids can function as positive modulators of the GABA-A receptor, resulting in antidepressant, anticonvulsant, anxiolytic, and anti-stress effects. GABA-active neurosteroids may also attenuate drug-seeking and drug self-administration behaviors (Spence, Guerin, & Goeders, 2016).
Relative Safety of Oxazepam and Other Benzodiazepine Drugs
According to U.S. data from the Centers for Disease Control and Prevention, overdose deaths involving benzodiazepine drugs rose from 0.58 (per 100,000 adults) in 1999 to 3.07 in 2013, although the fatality rate was stable from 2010 to 2013 (Bachhuber, Hennessy, Cunningham, & Starrels, 2016). These data do not specify the extent to which these fatalities may have been associated with the concurrent use of alcohol or other drugs, nor do they distinguish among different benzodiazepine drugs. Prescription Behavior Surveillance System data from eight U.S. states in 2013 found that benzodiazepine drugs are prescribed only approximately one half as often as opioid drugs, and prescribing rates for oxazepam represented <0.5% of all benzodiazepine drugs (Paulozzi, Strickler, Kreiner, & Koris, 2015).
Oxazepam doses up to 480 mg per day are safe (Griffiths, McLeod, Bigelow, Liebson, & Roache, 1984a). Drug accumulation does not occur using doses up to 300 mg per day in alcohol-dependent patients treated for alcohol withdrawal (Imbert, Marsot, Liachenko, & Simon, 2016). Alcohol plus diazepam is associated with a greater degree of sedation and poor coordination than alcohol plus oxazepam (Molander & Duvhok, 1976).
Serfaty and Masterton (1993) calculated the fatal toxicity indices of different benzodiazepine drugs in Britain using national prescribing data and mortality statistics. The overall fatality rate was 5.9 deaths per 1 million prescriptions for benzodiazepine drugs taken alone or with alcohol, but the group of anxiolytic drugs (e.g., oxazepam, diazepam) were less toxic than the group of hypnotic drugs (e.g., temazepam). Oxazepam was less toxic than average among anxiolytic drugs; the fatality rate for oxazepam alone was 1.1 and with alcohol was 1.0. Diazepam, chlordiazepoxide, and lorazepam were more toxic than average among anxiolytic drugs. Diazepam was especially toxic with concurrent alcohol use.
Buckley et al. (1995) evaluated the sedating effects in overdose of various benzodiazepine drugs. Among 303 patients who had ingested benzodiazepine drugs alone or in combination with alcohol, oxazepam was significantly less sedating than other drugs and fewer patients became comatose, even though a greater percentage of oxazepam patients had co-ingested alcohol.
The National Poison Data System (NPDS) 2014 report (Mowry, Spyker, Brooks, McMillan, & Schauben, 2015) has information on nonpharmaceutical and pharmaceutical exposures in approximately 2.2 million human cases in the United States, many involving exposure to multiple substances. The top five substance categories most frequently involved in fatal and non-fatal human exposures in 2014 were analgesic drugs (11.3%), cosmetics/personal care products (7.7%), household cleaning substances (7.7%), sedative/hypnotic/antipsychotic drugs (including benzodiazepine drugs; 5.9%), and antidepressant drugs (4.4%). Benzodiazepine drugs as a group were mentioned in 74,128 cases, of which 27,060 were single exposures to a benzodiazepine drug alone. A large majority of single benzodiazepine drug exposures were judged to be mild or moderate in severity. Serious outcomes (defined as moderate or major adverse effects or death) were reported in only 14% of the single benzodiazepine drug exposures (including 18 deaths).
In 2014, the NPDS documented 1,408 human pharmaceutical and non-pharmaceutical exposures resulting in death (Mowry et al., 2015). The majority of fatalities involved multiple substances. The first-ranked substance (judged most likely responsible for the death) was a pharmaceutical in 1,105 cases. These first-ranked pharmaceuticals included 391 analgesic drugs, 191 stimulants/street drugs, 188 cardiovascular drugs, 98 antidepressant drugs, and 77 sedative/hypnotic/antipsychotic drugs. The first-ranked pharmaceuticals include acetaminophen (112 cases), acetaminophen combination products (70 cases), quetiapine (22 cases), alprazolam (14 cases), temazepam (seven cases), diazepam (six cases), and clonazepam (four cases). Only one of the 1,408 deaths involved oxazepam (detected along with acetaminophen, two opioid drugs, and two other benzodiazepine drugs). Annual NPDS reports dating back to 1999 (access http://www.aapcc.org/annual-reports) confirm that oxazepam has been involved in few fatalities and always together with other substances.
The Drug Abuse Warning Network (DAWN), a program of the Federal Substance Abuse and Mental Health Services Administration, is a public health surveillance system that reports drug-related visits to hospital emergency departments. Data from the National Estimates of Drug-Related Emergency Department Visits for 2004–2011 can be reviewed on the DAWN website (access http://www.samhsa.gov/data/emergency-department-data-dawn). These data are reported for all visits, non-medical use of pharmaceuticals visits, and drug misuse and abuse visits. Oxazepam visit rates (per 100,000 population) are extremely low compared to alprazolam, lorazepam, clonazepam, and diazepam.
Abuse Liability of Oxazepam Compared to Other Benzodiazepine Drugs
Placebo-controlled studies have documented that diazepam has a significantly higher abuse liability than oxazepam (Griffiths et al., 1984a; Griffiths et al., 1984b). Epidemiological data also show that diazepam abuse uniformly exceeded oxazepam abuse on seven measures of drug abuse (Griffiths et al., 1984b). Various data sources suggest that oxazepam has a low abuse liability, whereas lorazepam, alprazolam, and diazepam have relatively high abuse liabilities (Griffiths & Wolf, 1990). Benzodiazepine drugs, especially alprazolam, are commonly co-ingested along with stimulants, cocaine, and opiate drugs (Bachhuber et al., 2016; Spence et al., 2016).
Iguchi, Handelsman, Bickel, and Griffiths (1993) surveyed patients at methadone maintenance clinics regarding lifetime use of 10 commonly used benzodiazepine and barbiturate medications. Chlorpromazine (Thorazine®) was included in the survey as a negative control medication. Diazepam, lorazepam, and alprazolam were frequently used to get “high” and for selling to produce income. By contrast, chlordiazepoxide and oxazepam were rated as being less likely to produce a “high” and were much less likely to be obtained for the purposes of getting “high” or for resale. Patients were also asked whether they obtained various drugs by prescription only, never by prescription, or from licit and illicit sources during their lifetime. By prescription only use was 66% for oxazepam, which was the highest rate among all benzodiazepine drugs. Fewer than 9% of patients using oxazepam by prescription reported obtaining the prescription for reasons other than what might considered “therapeutic.” Rates of obtaining prescriptions for non-therapeutic reasons were greater for all other benzodiazepine drugs.
In a placebo-controlled study, Preston, Bigelow, and Liebson (1985) evaluated the effects of hydromorphone (Dilaudid®), clonidine, and oxazepam on their ability to alleviate symptoms of opioid withdrawal and the extent and pattern of self-administration of these drugs during methadone detoxification in methadone-dependent patients. Oxazepam did not significantly decrease withdrawal symptoms and was not self-administered significantly more than placebo.
Oxazepam has a favorable safety and abuse liability profile, suggesting that it is an underutilized benzodiazepine drug. The superior safety and reduced abuse liability of oxazepam may be related to its pharmacology. Oxazepam is more slowly absorbed and enters the brain more slowly than other benzodiazepine drugs; it does not have active metabolites and does not accumulate with chronic dosing; its metabolism is not affected by age or by mild/moderate liver disease; and it is not prone to drug–drug interactions. Oxazepam also binds to the TSPO, which stimulates the synthesis of neurosteroids, and this effect may contribute to its reduced abuse liability. Because neurosteroids can positively modulate GABA-A receptor function, this effect has clinical implications for the use of oxazepam in the treatment of substance abuse and depression, which I will review in next month's column.
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