Alprazolam: interactions

Opioids and other CNS depressants

Combining alprazolam with opioids can produce profound sedation, respiratory depression, coma, and death [1]. The two drug classes act on different receptors — benzodiazepines at GABA-A sites, opioids mainly at mu receptors [1]. As with benzodiazepines generally, this combination carries the potential to significantly worsen opioid-related respiratory depression [1]. Alprazolam produces additive CNS depressant effects when combined with other CNS depressants [1].

CYP3A inhibitors

Alprazolam is metabolised primarily by hepatic microsomal oxidation [2]. Strong CYP3A inhibitors — ketoconazole and itraconazole are named, ritonavir is an exception — are contraindicated with alprazolam outright because of the effect on clearance and the resulting rise in concentration and adverse-reaction risk [1]. Moderate or weak CYP3A inhibitors may also increase alprazolam concentrations and adverse-reaction risk . Cimetidine, fluoxetine, fluvoxamine, and propoxyphene are specifically reported to impair alprazolam clearance [2], and fluvoxamine's inhibition of the same pathway is separately described as a mechanism for toxicity through elevated alprazolam concentration and enhanced CNS depression, as with CYP450 inhibitors and benzodiazepines generally [3].

What this means in practice

Misuse of benzodiazepines commonly involves combining them with other medications, alcohol, or illicit substances, and this combination pattern is tied to more serious adverse outcomes [1]. Clearance is already reduced in many older adults and in anyone with cirrhosis [2].

References

1. XANAX (alprazolam) tablet — FDA prescribing information — DailyMed (U.S. National Library of Medicine)
2. Clinical pharmacokinetics of alprazolam. Therapeutic implications — Clinical Pharmacokinetics (Springer)
3. Anxiolytics and Sedative-Hypnotics Toxicity - StatPearls — NCBI Bookshelf (US National Library of Medicine)