Association Between Benzodiazepine or Z-Drug Prescriptions and Drug-Related Poisonings Among Patients Receiving Buprenorphine Maintenance: A Case-Crossover Analysis.
- Authors
- Xu, Kevin Y; Borodovsky, Jacob T; Presnall, Ned; Mintz, Carrie M; Hartz, Sarah M; Bierut, Laura J; Grucza, Richard A
- Year
- 2021
- Journal
- The American journal of psychiatry
- PMID
- 33653119
- DOI
- 10.1176/appi.ajp.2020.20081174
- PMCID
- PMC8286284
OBJECTIVE: Persons with opioid use disorder who take benzodiazepines are at high risk for overdose. The objective of this study was to evaluate the association of benzodiazepine and Z-drug use with drug-related poisonings among patients receiving buprenorphine maintenance treatment. METHODS: A case-crossover study design was used to analyze prescription claims among persons ages 12-64 with opioid use disorder who had buprenorphine prescriptions and had claims data in the IBM MarketScan databases (2006-2016), encompassing 14,213,075 person-days of observation time for 23,036 individuals who experienced drug-related poisoning. The exposures were buprenorphine prescriptions and benzodiazepine or Z-drug prescriptions, standardized as daily diazepam-equivalent milligram doses and separated by pharmacologic properties (short-acting or long-acting benzodiazepines, Z-drugs). The outcome of interest was nonfatal drug-related poisoning. Conditional logistic regression was used to evaluate variation in benzodiazepine or Z-drug and buprenorphine use between poisoning and nonpoisoning days. RESULTS: Buprenorphine treatment days were associated with a nearly 40% reduction in the risk of poisoning events (odds ratio=0.63, 95% CI=0.60, 0.66) compared with nontreatment days, whereas benzodiazepine or Z-drug treatment days were associated with an 88% increase in the risk of such events (95% CI=1.78, 1.98). In stratified analyses by dose, we observed a 78% (95% CI=1.67, 1.88) and 122% (95% CI=2.03, 2.43) increase in poisonings associated with low-dose and high-dose benzodiazepine or Z-drug treatment days, respectively. High-dose, but not low-dose, benzodiazepine or Z-drug treatment was associated with increased poisonings in combination with buprenorphine cotreatment (odds ratio=1.64, 95% CI=1.39, 1.93), but this was lower than the odds risk associated with benzodiazepine or Z-drug treatment in the absence of buprenorphine (low-dose: odds ratio=1.69, 95% CI=1.60, 1.79; high-dose: odds ratio=2.23, 95% CI=2.04, 2.45). CONCLUSIONS: Increased risk of nonfatal drug-related poisoning is associated with benzodiazepine or Z-drug treatment in patients with opioid use disorder, but this risk is partially mitigated by buprenorphine treatment. Dose reduction of benzodiazepines or Z-drugs while maintaining buprenorphine treatment may provide the advantage of lowering drug-related poisoning risk.
shows derivation of the study’s final analytic sample during follow-up. There were 304,676 individuals ages 12 and older with a diagnosis of OUD, prescription drug coverage, and at least one OUD claim during period of enrollment. 234,957 individuals without drug related poisonings were excluded from the sample, resulting in 69,719 individuals (23%) with poisoning events that occurred between 2006 and 2016 in the MarketScan databases. We then excluded individuals who never received any opioid use disorder medication (naltrexone, methadone, buprenorphine), resulting in 33,083 individuals with both drug related poisonings and were taking OUD medications. We excluded individuals who never received buprenorphine, resulting in 25,091 individuals with poisoning events and insurance claims for buprenorphine coverage. Finally, we excluded person days of naltrexone and methadone treatment and narrowed our window of observation to up to 1 year before and after index poisoning.
provides an overview of the study’s case-crossover design. In this figure, treatment days during which an individual received a medication, such as, benzodiazepines or buprenorphine, that culminated in drug-related poisoning (hatched boxes) are compared to days that do not coincide with poisoning event for the same medication (shaded boxes). We used an observation period spanning up to at most one year before and after index poisoning. Consequently, each individual can potentially contribute multiple drug-related poisoning events to the final analysis, as long as such events fall within a maximum of one year before and after index poisoning event.For individual #1, Figure 2 depicts five treatment periods, two of which culminate in a drug-related poisoning. This contrasts with individual #2, who has two treatment periods, only one of which culminates in a drug-related poisoning; individual #2 has three drug-related poisonings, two of which are not preceded by medication treatment. Individuals #3 and #4 notably do not have any treatment periods culminating in drug-related poisoning.
| Name | Type |
|---|---|
| accidental-injury related emergency room visits local | phenotype |
| addictive potential | phenotype |
| adjacent person-days local | cohort |
| adults | cohort |
| alcohol | phenotype |
| all-cause mortality | phenotype |
| alprazolam local | drug |
| anxiety | phenotype |
| anxiety symptoms | phenotype |
| benzodiazepine agents local | drug |
| benzodiazepine nonusers local | cohort |
| benzodiazepines | drug |
| benzodiazepine users local | cohort |
| benzodiazepine + Z drug local | drug |
| buprenorphine | drug |
| Case period local | cohort |
| citalopram | drug |
| clonazepam | drug |
| Control period local | cohort |
| decreased retention in treatment local | phenotype |
| diazepam | drug |
| drug exposure | phenotype |
| drug-related poisoning local | phenotype |
| Drug-related poisoning local | phenotype |
| Drug-related Poisoning local | phenotype |
| drug-related poisonings local | phenotype |
| escitalopram | drug |
| eszopiclone local | drug |
| Final analytic sample local | cohort |
| fluoxetine | drug |
| High buprenorphine dose local | phenotype |
| high-dose benzodiazepine local | drug |
| High-dose Benzodiazepines local | drug |
| high-dose buprenorphine local | drug |
| higher-potency agents local | drug |
| IBM® MarketScan® Commercial Database local | cohort |
| IBM MarketScan databases local | cohort |
| illicit drugs | phenotype |
| Index poisoning local | phenotype |
| injury risk local | phenotype |
| insured patients local | cohort |
| long-acting benzodiazepine local | drug |
| Long-acting benzodiazepine local | drug |
| Long-acting sedative/hypnotic agents local | drug |
| Low buprenorphine dose local | phenotype |
| low-dose benzodiazepine local | drug |
| low-dose buprenorphine local | drug |
| MarketScan local | cohort |
| MarketScan data local | cohort |
| Methadone | drug |
| mood disorders | phenotype |
| mortality | phenotype |
| Multi-State Medicaid Database local | cohort |
| naloxone | drug |
| naltrexone | drug |
| non-fatal drug-related poisoning local | phenotype |
| Non-fatal drug-related poisoning local | phenotype |
| non-OUD populations local | cohort |
| non-overdose deaths local | phenotype |
| older adults | cohort |
| opioid | drug |
| opioid dependence | phenotype |
| Opioid maintenance treatment local | cohort |
| Opioid Use Disorder treatment local | drug |
| Opioid user population local | cohort |
| other substances | phenotype |
| OUD | phenotype |
| OUD cohort (ages 12-64) local | cohort |
| OUD outcomes local | phenotype |
| OUD patients local | cohort |
| overdose | phenotype |
| overdose deaths local | phenotype |
| Overdose events local | phenotype |
| participants | cohort |
| Participants with non-fatal drug-related poisonings local | cohort |
| patients receiving buprenorphine local | cohort |
| patients taking both benzodiazepines and buprenorphine local | cohort |
| Persons who never experienced poisonings local | cohort |
| Poisoning local | phenotype |
| poisoning deaths local | phenotype |
| psychotropic medication | drug |
| respiratory depression | phenotype |
| retention in buprenorphine maintenance treatment local | phenotype |
| Sedative/hypnotic local | drug |
| Sedative/hypnotic prescriptions local | drug |
| selective serotonin reuptake inhibitors | drug |
| sertraline | drug |
| short-acting benzodiazepine local | drug |
| Short-acting benzodiazepine local | drug |
| short-acting benzodiazepines local | drug |
| Short-acting Benzodiazepines local | drug |
| Short-acting sedative/hypnotic agents local | drug |
| SSRIs | drug |
| study cohort | cohort |
| substance use | phenotype |
| treatment failure | phenotype |
| treatment retention | phenotype |
| zaleplon | drug |
| Z drug local | drug |
| Z-drug local | drug |
| Z drugs local | drug |
| zolpidem | drug |
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