What is the justification for concomitant opioid and benzodiazepine (BZD) therapy?

Justification for Concomitant Opioid/Benzodiazepine Therapy

Concomitant opioid and benzodiazepine therapy should be reserved exclusively for patients in whom alternative treatment options are inadequate, as this combination increases overdose mortality risk 3- to 10-fold compared to opioids alone. 1, 2, 3

Evidence Against Routine Co-Prescribing

The FDA drug labels for both opioids and benzodiazepines explicitly state that profound sedation, respiratory depression, coma, and death may result from concomitant use 2, 3, 4. The mechanism involves:

• Opioids directly activate mu-opioid receptors on brainstem neurons controlling breathing, inducing respiratory depression 1
• Benzodiazepines cause CNS depression and decrease respiratory drive 5
• The combination produces substantial potentiation of respiratory depression beyond what either drug causes alone, creating life-threatening risk 1

Epidemiologic data demonstrates that benzodiazepines were present in 31-61% of fatal opioid overdose deaths 1. A case-cohort study found that concurrent benzodiazepine prescription with opioid prescription was associated with nearly quadrupling the risk for overdose death compared to opioid prescription alone 5, 6.

When Concomitant Use May Be Justified

The only acceptable justification is when alternative treatment options have been exhausted and proven inadequate 1, 2, 3, 4. This requires:

• Documented trials of non-benzodiazepine anxiolytics (SSRIs, SNRIs, buspirone, hydroxyzine) for anxiety 1, 6
• Optimization of the opioid regimen through dose adjustment, opioid rotation, or switching to non-opioid analgesics 1, 6
• Evidence-based psychotherapies such as cognitive behavioral therapy 7

One notable exception exists: in hospice and end-of-life care settings, benefits may outweigh risks when comfort is the primary goal 8. However, this represents a fundamentally different risk-benefit calculation than in other clinical contexts.

Mandatory Prescribing Safeguards

If the decision is made to co-prescribe, the following are non-negotiable 5, 1, 2, 3, 4:

• Prescribe the absolute lowest effective dosages of both medications 5, 1, 6
• Prescribe minimum durations of concomitant use 5, 1, 6
• In patients already receiving an opioid, prescribe a lower initial dose of the benzodiazepine than indicated in the absence of an opioid, and titrate based on clinical response 2, 3, 4
• In patients already taking a benzodiazepine, prescribe a lower initial dose of the opioid than indicated in the absence of a benzodiazepine, and titrate based on clinical response 2, 3, 4
• Check prescription drug monitoring programs (PDMPs) for concurrent controlled medications prescribed by other clinicians 7, 6
• Involve pharmacists and pain specialists as part of the management team 7, 6

High-Risk Populations Requiring Extra Caution

Certain populations face substantially elevated risk and require even more stringent precautions 1, 6:

• Elderly patients (≥65 years) have altered pharmacokinetics, reduced clearance, and smaller therapeutic windows 5, 1
• Patients with respiratory compromise (COPD, asthma, sleep apnea) are at heightened risk of respiratory depression 5, 1, 2
• Patients with hepatic impairment have reduced metabolism, increasing toxicity risk 5, 6

Patient Education and Naloxone

All patients receiving concomitant therapy must receive 5, 6:

• Counseling about signs of respiratory depression (slow or shallow breathing, extreme drowsiness, inability to wake) 1, 6
• Warnings to avoid alcohol and other CNS depressants 7, 2
• Naloxone prescription with instruction in its use 1
• Explicit warnings not to drive or operate heavy machinery until effects are determined 2

Tapering Strategy When Discontinuing

When reducing this combination to minimize risk 7, 6:

• Taper opioids first, then benzodiazepines, as benzodiazepine withdrawal carries greater risks including seizures, delirium tremens, and death 7, 6
• Taper benzodiazepines gradually by 25% every 1-2 weeks to avoid withdrawal symptoms 7, 6
• Consider cognitive behavioral therapy to increase tapering success rates 7

Clinical Reality

Despite guidelines and quality measures, patients continue to use opioids and benzodiazepines concurrently 9. Those with concurrent use demonstrate higher rates of mood disorders, depression, risky opioid-related behaviors (higher daily doses, multiple prescribers/pharmacies), and significantly higher rates of emergency department visits and hospitalizations 9. The most common patient-reported reason for benzodiazepine use is anxiety management, though many also report using benzodiazepines to enhance opioid effects or manage withdrawal 10.