Benzodiazepine and Opioid Co-Prescribing Risks

Introduction to Risks

The American College of Emergency Physicians notes that benzodiazepines substantially potentiate opioid-related respiratory depression, increasing the risk of fatal overdose by 3- to 10-fold compared to opioids alone 1

Opioids activate mu-opioid receptors on brainstem neurons that control breathing, directly inducing respiratory depression, as stated by the Annual Review of Medicine 2
The combination of opioids and benzodiazepines produces substantial potentiation of respiratory depression beyond what either drug causes alone, creating life-threatening risk, according to the Annals of Emergency Medicine 1

The Centers for Disease Control and Prevention (CDC) found that rates of death are 3- to 10-fold higher in patients co-prescribed opioids and benzodiazepines compared with opioids alone 1
Benzodiazepines were found in 31-61% of fatal opioid overdose deaths, as reported by the MMWR Recommendations and Reports 3, 4

The American Academy of Pain Medicine recommends reserving concomitant prescribing for patients for whom alternative treatment options are inadequate 1
The Annual Review of Medicine suggests using the absolute lowest effective dosages of both medications and prescribing minimum durations of concomitant use 2, 3, 4, 5

The National Institute on Aging notes that elderly patients (≥65 years) have altered pharmacokinetics, reduced clearance, and a smaller therapeutic window, substantially increasing overdose risk 3, 4, 5
The American Thoracic Society states that patients with respiratory compromise (COPD, asthma, sleep apnea) are at heightened risk of respiratory depression 2, 3, 4, 5

The American Psychiatric Association recommends considering SSRIs, SNRIs, buspirone, or hydroxyzine as first-line options instead of benzodiazepines for anxiety 6, 5
The American Academy of Pain Medicine suggests optimizing the opioid regimen first through dose adjustment, opioid rotation, or switching to non-opioid analgesics 5

The Substance Abuse and Mental Health Services Administration (SAMHSA) advises counseling patients and caregivers about signs of respiratory depression (slow or shallow breathing, extreme drowsiness, inability to wake) 5
The CDC recommends prescribing naloxone and providing instruction in its use for patients at elevated overdose risk 2, 5

The Centers for Disease Control and Prevention recommends evidence-based psychotherapies such as cognitive behavioral therapy for patients receiving concomitant opioid and benzodiazepine therapy 7
The Centers for Disease Control and Prevention suggests checking prescription drug monitoring programs (PDMPs) for concurrent controlled medications prescribed by other clinicians 7
The Centers for Disease Control and Prevention advises involving pharmacists and pain specialists as part of the management team 7
The Centers for Disease Control and Prevention recommends warning patients to avoid alcohol and other CNS depressants 7
The Centers for Disease Control and Prevention suggests prescribing naloxone with instruction in its use for patients receiving concomitant therapy 7
The Centers for Disease Control and Prevention recommends tapering opioids first, then benzodiazepines, when discontinuing concomitant therapy 7
The Centers for Disease Control and Prevention advises tapering benzodiazepines gradually by 25% every 1-2 weeks to avoid withdrawal symptoms 7
The Centers for Disease Control and Prevention suggests considering cognitive behavioral therapy to increase tapering success rates 7