Sublingual use of benzodiazepines
pubmed.ncbi.nlm.nih.gov
TO THE EDITOR: Benzodiazepines, available in oral, intravenous, and intramuscular dosage forms, are widely used in the treatment of anxiety, insomnia, and muscle spasms. Some of these agents are also employed in preoperative sedation and in the management of various seizure disorders. The sublingual use of two benzodiazepines (lorazepam and triazolam) was recently described in a review by Sussman.' That information, however, was based on anecdotal reports, according to the author (personal communication, Norman Sussman, M.D., New York University School of Medicine, April 1985).
Reports regarding this unique mode of benzodiazepine administration have been few. Caille and colleagues studied the pharmacokinetic properties of various lorazepam formulations, each given as asingle 2-mg dose! Sublingually administered lorazepam was absorbed more rapidly than that given orally. Furthermore, the sublingual route compared favorably with intramuscular injection into the deltoid muscle. It should be noted that three distinct tablet formulations were tested sublingually, one of which was the trade oral tablet. The absorption of the trade oral tablet when given sub lingually was superior to the same tablet given orally, but was somewhat inferior to a special sublingual tablet. Using the intramuscular preparation as the reference standard, the bioavailability of the oral tablet was higher when administered orally rather than sublingually. The same tablet, when given orally, was slightly more bioavailable than the standard intramuscular form, as was the special sublingual tablet.
Greenblatt and associates in a similar study reported rapid and nearly complete absorption of lorazepam given sublingually either as the trade oral tablet or a specially formulated sublingual tablet using single 2-mg doses. Orally administered lorazepam was comparable with that given by the sublingual route. The intramuscular injection into the deltoid muscle was found to be the most rapidly absorbed of the three preparations, but differences in absorption were reportedly not significant. Gale et al. tested the efficacy of a sublingual preparation of lorazepam against an intramuscular injection of the same as premedication for 150 patients undergoing minor gynecological surgery. A single dose ranging from 2 to 4 rng was selected depending on the patient's weight. Those receiving the drug sublingually had less recall, an earlier onset of sedation, more drowsiness, and a longer recovery time than those who received the drug intramuscularly. The authors concluded that sublingual lorazepam was superior due to its rapid absorption resulting in more drowsiness and amnesia.' It is not known, however, whether the sublingual preparation used in this study was the trade oral tablet or a specially formulated sublingual tablet.
The delivery of lorazepam and other benzodiazepines by the sublingual route may offer significant advantages and increase their versatility. The trade oral tablet currently available in the U.S. is rapidly and nearly completely absorbed from both the oral mucosa and the gastrointestinal tract and, when used sublingually, compares favorably with intramuscular administration. Sublingual use may eliminate the need for intramuscular injections, which are often associated with pain and discomfort. The intramuscular form also requires refrigeration, has a short shelf-life, and is more expensive than oral tablets.' The sublingual route may also be used in patients who are unable to swallow, regardless of the etiology. A more attractive use of sublingual lorazepam may be in patients who are allowed nothing by mouth for whom parenteral administration is the only current alternative. In view of these possible benefits, we believe that the sublingual use of lorazepam and other benzodiazepines warrants further study to correlate pharmacokinetic data with concrete clinical evidence of efficacy.
KARIM A. CALIS, B.S.Pharm.
Pharm.D. Student
School of Pharmacy
University of Maryland
Baltimore, Maryland 21201
RITA A. MITSCH, Pharm.D.
Clinical Assistant Professor
School of Pharmacy
University of Maryland, and
Clinical Pharmacist
Franklin Square Hospital
Baltimore, Maryland 21237
I've tried around 30 different benzodiazepines and in every single case onset is comparable to IM injection. Pyrazolam was specifically designed to be water soluble as we initially intended to produce sublingual films BUT the only manufacturer able to produce the films was based in Japan and the lead-time was about 8 months. Too long since we had no idea how long it would take a Chinese vendor to offer a knock-off version. We need not have worried. I've been shown samples of Chinese-made pyrazolam and in every case it was yellow suggesting the presence of the intermediate thioamide. Now the thioamide isn't toxic BUT anyone who is happy to allow an impure produce is just as likely to leave the intermediate acetyl hydrazide and that most certainly IS something to be concerned about.
In nations like India sublingual clonazepam (banana flavoured) is produced for children. I do not think making tablets taste 'nice' is conducive to safety but their you go, it's not a guess, not even an educated guess. In fact, I note online that 'banana klonapin' was noted by people buying from shady sources.
BTW oral bioavailability of benzodiazepines is still very high but pyrazolam was specifically designed to be a selective anxiolytic with a fast onset and believe me, 1mg of the powder under the tongue worked in a matter of seconds and any you do swallow still winds up with 83% (oral) bioavailability.