Chris Aiken, MD.
Editor-in-Chief of The Carlat Psychiatry Report
Lorazepam (Ativan) received a new coating this year as Loreev XR, which promises a 24-hour duration for this benzodiazepine that is otherwise divided in two or three daily doses. It joins alprazolam (Xanax) as the only benzos with extended-release (XR) formulations (clorazepate ventured into this territory as Tranxene SD in 2002, but that medication is no longer manufactured).
For patients who require 24-hour coverage, these formulations offer convenience and—in theory—better tolerability and lower abuse liability. How well does that theory pan out? For lorazepam XR, we can only guess, as the approval was based on pharmacokinetic data in healthy volunteers and the drug lacks clinical studies. For alprazolam XR, a small trial does bear it out.
Fourteen men with a history of sedative abuse were given blinded samples of alprazolam XR, alprazolam instant release (IR), and placebo. When asked how much they were willing to pay for another dose, XR and placebo earned the same valuation, but IR attracted a higher price (no money was exchanged in the study). Side effects also looked better with XR, which—unlike IR—did not impair cognitive or motor function (Mumford GK et al, Clin Pharmacol Ther 1995;57(3):356–365).
Lorazepam XR’s pharmacokinetics suggest it may have similar advantages. Alprazolam and lorazepam peak in 1.5–2 hours in their IR forms, while the XRs have a longer delay: nine hours for alprazolam XR and 14 hours for lorazepam XR. The two XRs differ, however, in how they interact with food. Lorazepam XR lacks food interactions, but a high-fat meal will cause alprazolam XR to release its contents faster, resulting in a faster speed of onset and—potentially—withdrawal effects before the next dose is due.
Alprazolam XR has the advantage of FDA approval in panic disorder (typical dose 2–5 mg/day, maximum 10 mg/day), an approval shared only by clonazepam (typical dose 1–2 mg/day, maximum 4 mg/day). Panic disorder is the best-studied indication for benzodiazepines and one where 24/7 coverage is sometimes needed for patients to function.
Lorazepam, however, has advantages of its own. It lacks hepatic drug interactions and does not form active metabolites, making it potentially safer in the elderly and medically ill. It also has one of the lowest toxicity indexes among the benzos, a quality that’s particularly relevant given the new warnings about accidental overdoses when benzodiazepines are taken with opioids. Alprazolam’s toxicity index is one of the highest (Buckley NA and McManus PR, Drug Saf 2004;27(2):135–141). However, the risk of dangerous opioid interactions is higher with long half-lives and XR formulations, so the IR formulation is preferable for the rare cases where a benzo and an opioid must be taken together.
Lorazepam XR is available as 1, 2, and 3 mg capsules that can be opened and sprinkled on food. It is dosed once in the morning at a monthly cost of $300.
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