Predictors of Incident Benzodiazepine Co-prescription Among Patients Prescribed Long-term Opioids

Opioid and benzodiazepine co-prescription is associated with overdose, particularly among patients prescribed long-term opioids.

Identify predictors of incident benzodiazepine and opioid co-prescription using two separate and complementary large-scale patient cohorts.

Two retrospective cohort studies: (a) statewide dataset based on California's prescription drug monitoring program (PDMP, 7/1/2016-12/1/2018) and (b) national sample of commercial and Medicare Advantage enrollees from the Optum Labs Data Warehouse (OLDW, 7/1/2016-12/1/2021).

Patients prescribed long-term opioids, with opioid coverage for ≥ 80% (≥ 144 days) of a 180-day baseline period absent baseline benzodiazepine or buprenorphine prescriptions. OLDW cohort excluded patients without continuous enrollment, with cancer diagnoses or use of hospice or prolonged inpatient skilled nursing care.

Incident benzodiazepine and opioid co-prescription (≥ 20 days of co-prescription during any 30-day period).

Of 617,946 and 223,885 patients, incidence rates of co-prescription were 4.6 and 3.9 cases per 1000 patient-months in the PDMP and OLDW cohorts, respectively. Important predictors included patients prescribed > 150 mg morphine equivalents daily during baseline (PDMP, adjusted hazard ratio: 1.74 [95% CI: 1.67-1.81]; OLDW: 2.66 [2.47-2.86]), and initiated buprenorphine indicated for treatment of opioid use disorder, with (PDMP: 1.68 [1.49-1.89]; OLDW: 2.10 [1.71-2.59]) or without continued treatment (PDMP: 1.35 [1.18-1.56]; OLDW: 1.64 [1.27-2.11]). Co-prescription was positively associated with short-term (60-day) decreases in opioid dose (PDMP: 1.07 [1.04-1.10]; OLDW: 1.06 [1.01-1.12]) but negatively associated with long-term (180-day) decreases (PDMP: 0.81 [0.78-0.85]; OLDW: 0.78 [0.73-0.84]). Patients with anxiety diagnoses were at elevated risk for co-prescription (OLDW: 2.16 [2.06-2.27]), although risk was lower if accompanied by treatment with serotonergic anxiolytics (0.63 [0.59-0.67]).

High baseline opioid dose, buprenorphine initiation, short-term decrease in opioid dose, and anxiety without prescriptions for serotonergic anxiolytics were positively associated with co-prescription. A longer-term decrease in opioid dose and anxiety treated with serotonergic anxiolytics were negatively associated with co-prescription.