Off-Label use of Midazolam in randomized controlled trials


      Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or form of administration (1). The goal of this study is to investigate the data regarding the off-label use of midazolam; a versatile benzodiazepine, in randomized controlled trials (RCTs).

      Material and Methods

      RCTs of were identified retrospectively through a search of PubMed from March 2012 to the past (1981) using the search term ‘midazolam’. Identified articles were screened for purpose or indication of the midazolam use, on/off label use, age of patients, route and location of administration. On-label criteria were based on information provided by the manufacturer of midazolam.


      A total of 1081 RCTs of midazolam were detected; 314 were off-label and 276 were conducted in children. Until 1989 the number of RCTs per year was under 20 and from 1990 to 2011 the average of RCTs was 43.4 (31-54) per year. Most common on-label indication was to provide sedation and induction of anesthesia. Common fields of research were induction of anesthesia and/or anesthetic effect/technique, evaluation of pharmacokinetics and pharmacodynamics. The routes used for off-label administration were intranasal, intrathecal, sublingual and rectal route. The common subjects for off-label research were the anticonvulsant, antiemetic, anti-shivering effects of midazolam and the use as an adjunct to local anesthetics.


      Off-label use of midazolam occurs frequently in the RCTs. Although it is legal to prescribe drugs off-label, there may be health risks and differences in legal liability. There is need to generate evidence-based and safe scientific basis regarding every aspects of clinical conditions during the processes of approving and labeling.


      1. Stafford RS. Regulating off-label drug use- rethinking the role of FDA. N Engl J Med. 2008;358:1427–1429.