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Ask the Expert: Multiple Benzo Prescriptions

July 2014

A patient requested refills for 2 benzodiazepine agents at the same time (alprazolam and clonazepam).  Is this ever appropriate?


Benzodiazepines are used in the treatment of multiple disease states. They may be prescribed as anxiolytics, muscle relaxants, procedural sedation agents, or sedative-hypnotics to treat withdrawal states or hyperadrenergic/stimulated conditions (seizures, insomnia, serotonin syndrome, neuroleptic malignant syndrome, sympathomimetic overdose, or psychiatric conditions).1

Benzodiazepines are thought to exert most of their effects by interacting with inhibitory neurotransmitter receptors directly activated by γ-aminobutyric acid (GABA). GABA is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA also is directly responsible for the regulation of muscle tone. Benzodiazepines enhance the effect of GABA at the GABAA receptor, resulting in sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties.2

The major clinical advantages of benzodiazepines are that they have a rapid onset of action to effectively treat the disease states that they are used in. However, with longterm use, tolerance, dependence, and withdrawal effects can become major disadvantages.

Pharmacokinetic Profiles Vary

Benzodiazepines differ significantly in potency, lipophili-city, elimination half-lives, and onset and duration of action. These differences make up the difference in their clinical utility and give rise to 3 categories of benzodiazepines: short-acting, intermediate-acting, and long-acting agents.1,2 Table 1 describes the pharmacokinetic differences between the benzodiazepines.

Except for oxazepam, lorazepam, and temazepam, the metabolism of benzodiazepine agents is extensively through the cytochrome P (CYP) 3A4 and CYP 2C19 enzymes.2 Therefore, when benzodiazepines are given together, they may compete for the same substrates of metabolism, which may lead to larger plasma concentrations. Metabolism is further complicated in the elderly, in whom volumes of distribution change for these drugs, leading to accumulation and toxicity.1,2 Various other drug interactions exist, further complicating the true plasma concentrations of benzodiazepines.

What the Guidelines Say

Several clinical practice guidelines recommend the use of benzodiazepines as a treatment option for various disease states. Guidelines for the treatment of anxiety, obsessive-compulsive, and post-traumatic stress disorders from the American Psychiatric Association, National Institute for Health and Clinical Excellence (NICE), and the World Federation of Societies of Biological Psychiatry (WFSBP) state that the use of benzodiazepines should be reserved for treatment-resistant cases and should not be offered for treatment except as a short-term measure during a crisis, or during the first weeks of serotonergic medication initiation to suppress increased anxiety.3-5 When prescribed, benzodiazepines should be used in a regular dosing regimen and not on an as needed basis. As needed use only is recommended in the treatment of short-term distress (eg, air travel or dental procedures).3-5

The American Academy of Sleep Medicine states that benzodiazepines mainly are indicated for patients with primary insomnia (psychophysiologic, idiopathic, or paradoxical ICSD-2 subtypes). The recommended treatment options are short- and intermediate-acting benzodiazepine receptor agonists (benzodiazepines and nonbenzodiazepine hypnotics) or the melatonin receptor agonist ramelteon (Rozerem). Examples of the nonbenzodiazepine medications include zolpidem (Ambien, others), eszopiclone (Lunesta), and zaleplon (Sonata). Benzodiazepines not specifically approved for insomnia (eg, lorazepam, clonazepam) also might be considered if the duration of action is appropriate for the patient’s presentation or if the patient has a comorbid condition that might benefit from these drugs.6

Benzodiazepines are recommended as first-line agents in the emergent initial treatment of epilepsy. Buccal midazolam, rectal diazepam, and intravenous lorazepam are first-line antiepileptic agents for prolonged or repeated seizures and convulsive status epilepticus in community and hospital settings. Clobazam (Onfi) and clonazepam (Klonopin) also are recommended as adjunctive treatment for many different epilepsy disorders including: generalized tonic-clonic, absence, myoclonic, focal, and childhood absence epilepsy, as well as juvenile absence seizures.7,8

Benzodiazepines commonly are used as muscle relaxants, though they are not approved by the US Food and Drug Administration for this indication. Guidelines for the management of chronic, non-specific low back pain from both the American and European pain societies recommend the limited usage of benzodiazepines as muscle relaxants. They may be considered for short-term pain relief in chronic lower back pain but should be used with caution due to their side effects. Benzodiazepines do not appear to exert their effect by reducing muscle spasm, and pain-relieving drugs with fewer side effects should be considered first.9,10


The pharmacology and pharmacokinetics of benzodiazepines suggest that concomitant use of more than one benzodiazepine at a time may lead to an increased risk of toxicity. When benzodiazepines are included as a treatment option in clinical practice guidelines, other more effective and less toxic agents are recommended prior to benzodiazepine use, and the lowest effective dose for the shortest duration is recommended. Therefore, there exists no clear evidence supporting the use of multiple benzodiazepine agents in combination to produce better clinical outcomes. Safety concerns appear to outweigh potential benefit. Individual patient needs always should be considered and appropriate care may require treatment not supported fully by guidelines; however, the potential for benefit always should be weighed against the potential for toxicity.


Last updated on: May 19, 2015
First published on: July 1, 2014