This is first in the three part blog series on benzodiazepines and their dangers in combination with opioid drugs. This blog provides an overview of the drug class, its adverse effects, and pharmacologic interactions with the opioid medications. Part two will focus on the clinical interaction of benzodiazepines and opioid medications. Part three will provide an introduction to the new Partnership HealthPlan initiative to reduce benzo use in members also on opioids.

The benzodiazepines (‘benzos’) are one of the most frequently used psychotropic medications in the United States. This drug class was discovered in 1955 with the chlordiazepoxide (Librium) put onto the market. Within 20 years, drugs in this class were the most widely prescribed medication.  These drugs are a combination of a benzene moiety and a diazepine moiety that together act as a positive modulator of the gamma-aminobutyric acid (GABA) system in the brain. Their popularity in practice stems from their treatment effectiveness for a variety of psychiatric and neurologic diseases including anxiety disorders, panic disease, insomnia, alcohol withdrawal and seizure disorders. Their primary effect is sedation, muscle relaxation, and anxiolysis. These positive effects and ready availability create a perfect storm for abuse and addiction.

These drugs have serious adverse complications including over-sedation, decreased cognition and worsening of memory (note that benzodiazepines are on the Beers List), dyscoordination and increased fall risk, hypoventilation, and depression.

This drug class has varying pharmokinetic profiles and can be broken into three categories based upon their half-life:

  • Short acting benzos have a median half-life of 1-12 hrs. Examples- midazolam, triazolam


  • Intermediate acting benzos have a median half-life of 12-40 hrs. Unlike the short acting, they have residual effects. Examples- alprazolam, lorazepam, temazepam, clonazepam


  • Long acting benzos have a median half-life of 40-250 hrs. Although they have less rebound and withdrawal effects than the intermediate versions, they can accumulate and cause long term impairments. Examples- diazepam, chlordiazepoxide, flurazepam

Research has demonstrated that benzos are inhibitors of opioid metabolism, although this finding has been questioned for its clinical significance. Studies have found that the analgesic effect of benzos are mediated through the opioid receptor system in the brain. These findings suggest that individuals use benzos to amplify the u receptor response to opioids. One evidence of this interaction was a study in 1984 that the combination of oral diazepam with methadone produced greater pupillary constriction than either drug alone. Note that benzos have no independent effect on pupillary constriction. In real world settings, patients on stable doses of opioids rate their level of ‘high’ as greater when given a benzo.


As will be discussed in the next blog in this series, the polydrug combination of opioids and benzos is a significant predictor of overdose. For instance, over 60% of patients being treated for opioid overdose had a benzo in their urine as well. This percentage increases when only fatal overdoses are examined. In this setting, over 70% of fatal opioid overdoses have a benzo in their system at the time of death.


Jones JD; Mogali S; Comer SD. “Polydrug Abuse: A Review of Opioid and Benzodiazepine Combination Use.”  Drug and Alcohol Dependence, 2012, 125(1-2) 8-18


Next in Series:

#2: How the Benzo-Opioid Combination complicates management

#3: PHC’s Response to Members on Benzo-Opioid Combination

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