Association between hypnotics use and increased mortality: causation or confounding?

Many research studies have found associations between benzodiazepines and/or z-hypnotics (BZZ) and increasing mortality, leading to a discussion about causation or confounding. This study suggests a factor that could produce this association through confounding.

The Norwegian population in 2010 supplied 8862 deaths ages 41-80 and 898,289 controls. Index dates were added to control records which corresponded to death dates. BZZ use was recorded for 2 years before death/index date.

Persons exposed to BZZ were more likely (OR = 2.3) to die than those who were not. With proximity of death, increasingly larger proportions of the prospective deaths received prescriptions for BZZ, until in the last 2 months 40-45% received BZZ. The frequency of BZZ use in controls increased with age as opposed to the death cohort where all ages showed similar rates of BZZ use. In the last few months before death, the youngest age group had an OR = 5.8 for BZZ use while the oldest age group an OR = 1.8, adjusted for age and sex. Opioid use showed a similar pattern of increasing use near death.

The increased use of BZZ with approaching death is consistent with increasing symptomatic treatment in terminal illness. Thus, the association of BZZ and mortality is more likely to be due to confounding than to causality. Further evidence from this and other research includes similar use patterns for other drugs such as opioids, the lack of specificity in cause of death and the size of the association regarding age and time to death.