November 2015

Benzodiazepines

Dr. Joseph E. Graas, Scientific Director
Dr. Edward Moore, Medical Director

The benzodiazepines are one of the main substances tested for in treatment centers as a drug of abuse.  They interact additively with other drugs both pharmaceutical and those of abuse.  The combination of benzodiazepines and opiates, especially heroin, are often a cause of fatalities.  They were reported as the largest group of recreationally used drugs in 19971, and remain one of the most abused.

The first benzodiazepine, chlordiazepoxide (Librium®), was discovered serendipitously in 1954 by the Austrian scientist Dr. Leo Sternbach (1908-2005), working for the pharmaceutical company Hoffmann-La Roche.2  Initially, he discontinued his work on the compound Ro-5-0690, but he “rediscovered” it in 1957 when an assistant was cleaning up the laboratory. Although initially discouraged by his employer, Sternbach conducted further research that revealed the compound was a very effective tranquilizer.

They began to be widely prescribed for stress-related ailments in the 1960s and 1970s.  In 1963 approval for use was given to diazepam (Valium) – a simplified version of Librium – primarily to counteract anxiety symptoms. Nitrazepam (Mogadon) was introduced in 1965 and flurazepam (Dalmane) in 1973 to assist in addressing sleep related problems.

Mechanism of Action

They are believed to act on the GABA receptor GABAA, the activation of which dampens higher neuronal activity by stimulating inhibitory neurons.

Classifications

Benzodiazepines are commonly divided into three groups: Short-acting compounds act for less than six hours and have few residual effects if taken before bedtime, but rebound insomnia may occur and they might cause wake-time anxiety. Intermediate-acting compounds have an effect for 6-10 hours, may have mild residual effects but rebound insomnia is not common. Long-acting compounds have strong sedative effects that persist. Accumulation may occur.

The various benzodiazepines listed are in order of the shortest acting to the longest acting (by the approximate elimination half-life of the drug), however this time may greatly vary between persons.

  • triazolam (Halcion®) – 2 hours
  • midazolam (Versed®, Hypnovel®) – 2-6 hours
  • oxazepam (Serax®) – 4-15 hours
  • chlordiazepoxide (Librium®) – 5-25 hours
  • alprazolam (Xanax®) – 6-12 hours
  • temazepam (Restoril®) 8-20 hours
  • lorazepam (Ativan®) 10-20 hours
  • bromazepam (Lexotan®) 10-20 hours
  • estazolam (ProSom®) 10-24 hours
  • lunitrazepam (Rohypnol®) 18-26 hours. (Withdrawn from the market in some countries; considered a “date-rape drug”)
  • clonazepam (Klonopin®, Rivotril®) 18-50 hours
  • nitrazepam (Mogadon®) 20-40 hours
  • quazepam (Doral®) 25-100 hours
  • clorazepate (Tranxene®) 36-100 hours
  • medazepam (Nobrium®) 36-150 hours
  • razepam (Centrax®) 36-200 hours
  • diazepam (Valium®) 36-200 hours
  • flurazepam (Dalmane®) 40-250 hours

The following are not benzodiazepines, but have similar effects:

  • zolpidem (Ambien®)
  • zaleplon (Sonata®)
  • meprobamate (Miltown®)

Part 2 of this article will appear in the December issue of Toxicology Times.

References

  1. Gerada C, Ashworth M. “ABC of mental health. Addiction and dependence–I: Illicit drugs”; BMJ 1997; 315:297-300. Fulltext. PMID 9274553.
  2. Sternbach LH. “The Discovery of Librium”; Agents Actions 1972; 2:193-6. PMID 4557348