Do benzodiazepines (BZDs) potentiate the effects of opioids?

Do Benzodiazepines Potentiate Opioids?

Yes, benzodiazepines substantially potentiate opioid-related respiratory depression, increasing the risk of fatal overdose by 3- to 10-fold compared to opioids alone. 1

Mechanism of Potentiation

Benzodiazepines and opioids act synergistically on the central nervous system through different but complementary mechanisms:

• Opioids activate mu-opioid receptors (MORs) on brainstem neurons that control breathing, directly inducing respiratory depression. 1
• Benzodiazepines enhance GABA-mediated inhibition, causing CNS depression and further decreasing respiratory drive. 1, 2
• The combination produces substantial potentiation of respiratory depression beyond what either drug causes alone, creating life-threatening risk. 1, 2

Mortality and Morbidity Evidence

The evidence for increased mortality with co-administration is robust and consistent:

• 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. 1
• A case-cohort study demonstrated that concurrent benzodiazepine prescription with opioid prescription nearly quadrupled the risk for overdose death compared to opioid prescription alone. 3
• Patients exposed to opioids and benzodiazepines were 20% more likely to have an opioid-related overdose than those exposed to opioids only, and those exposed to all three classes (opioids, benzodiazepines, and non-benzodiazepine sedative-hypnotics) were 60% more likely to overdose. 4
• Recent research confirmed benzodiazepine receipt during buprenorphine treatment was associated with a 2.92-fold increased risk of fatal opioid overdose and a 2.05-fold increased risk of non-fatal opioid overdose. 5

FDA Black Box Warning

The FDA issued a black box warning in 2016 specifically against opioid-benzodiazepine co-prescribing, highlighting the dangers of this combination. 6, 2

The FDA label for morphine explicitly states:

• "Profound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate tablets with benzodiazepines or other CNS depressants." 2
• "Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone." 2

Clinical Implications and Prescribing Guidance

When co-prescribing cannot be avoided:

• Reserve concomitant prescribing for patients for whom alternative treatment options are inadequate. 1, 2
• Use the absolute lowest effective dosages of both medications and prescribe minimum durations of concomitant use. 1, 7
• Prescribe a lower initial dose of the benzodiazepine than indicated in the absence of an opioid, and titrate based on clinical response. 2
• If initiating an opioid in a patient already taking a benzodiazepine, prescribe a lower initial dose of the opioid and titrate based on clinical response. 2
• Monitor closely for excessive sedation, respiratory depression, dizziness, confusion, and cognitive impairment at every clinical encounter. 6, 7, 2

High-Risk Populations

Certain patients face disproportionately elevated risk:

• Elderly patients (≥65 years) have altered pharmacokinetics, reduced clearance, and a smaller therapeutic window, substantially increasing overdose risk. 1, 7
• Patients with respiratory compromise (COPD, asthma, sleep apnea) are at heightened risk of respiratory depression. 1, 7, 2
• Patients with hepatic or renal impairment have reduced drug metabolism, leading to higher and longer-lasting drug levels. 1, 7
• Patients with substance use disorders, depression, or prior overdose history face significantly increased risk. 1, 7

Safer Alternatives

Before resorting to combination therapy, optimize each medication individually and explore non-benzodiazepine alternatives:

• For anxiety, consider SSRIs, SNRIs, buspirone, or hydroxyzine as first-line options instead of benzodiazepines. 6, 7
• For pain, optimize the opioid regimen first through dose adjustment, opioid rotation, or switching to non-opioid analgesics. 7
• Recent meta-analyses suggest that for acute low back pain, combination pharmacotherapy does not outperform NSAID monotherapy and may increase patient harm. 1

Common Pitfalls to Avoid

• Do not prescribe benzodiazepines reflexively without first optimizing opioid dosing or exploring non-benzodiazepine anxiolytic options. 6
• Do not fail to check prescription drug monitoring programs (PDMPs) for concurrent controlled medications prescribed by other clinicians. 7
• Do not underestimate the risk in patients who appear stable—respiratory depression can occur at any time, with greatest risk during initiation or dose increases. 2

Discontinuation Strategy

If tapering is necessary to reduce risk:

• It is generally safer to taper opioids before benzodiazepines due to greater risks of benzodiazepine withdrawal, including seizures and delirium tremens. 3, 7
• Taper benzodiazepines gradually (typically 25% reduction every 1-2 weeks) to avoid withdrawal symptoms including rebound anxiety, hallucinations, and seizures. 6, 3, 7
• Monitor for rebound anxiety, insomnia, and potential seizure activity during benzodiazepine taper. 6

Patient Education and Naloxone

• Counsel patients and caregivers about signs of respiratory depression (slow or shallow breathing, extreme drowsiness, inability to wake). 7, 2
• Advise patients to avoid alcohol and other CNS depressants. 7, 2
• Prescribe naloxone and provide instruction in its use for patients at elevated overdose risk. 1, 7

Multidisciplinary Management

Involve pharmacists, pain specialists, mental health professionals, and substance use disorder specialists in the management of this high-risk combination. 6, 3, 7