What is the safest benzodiazepine to use with Suboxone (buprenorphine/naloxone)?

Avoiding Benzodiazepines with Suboxone is the Safest Approach

The safest approach is to avoid prescribing benzodiazepines altogether when a patient is taking Suboxone (buprenorphine/naloxone), as the FDA has issued a black box warning about life-threatening respiratory depression and death from this combination. 1

Critical Safety Warnings

The combination of buprenorphine and benzodiazepines carries severe risks:

• Life-threatening respiratory depression and death have occurred when buprenorphine is combined with benzodiazepines or other CNS depressants 1
• The FDA explicitly warns patients of the potential danger of self-administration of benzodiazepines while under treatment with buprenorphine/naloxone 1
• Studies demonstrate a 3- to 10-fold higher risk of death when benzodiazepines are prescribed with opioid medications compared to either agent alone 2
• In clinical studies, when benzodiazepines were combined with opioids, hypoxemia occurred in 92% of subjects and apnea occurred in 50%, demonstrating dangerous synergistic respiratory effects 2

If Benzodiazepines Must Be Used: Relative Safety Profile

When benzodiazepines cannot be avoided despite the serious risks, the evidence suggests differential effects:

Lower-Risk Options (Based on Limited Evidence)

Oxazepam or lorazepam may be relatively safer choices if a benzodiazepine is absolutely necessary:

• Lorazepam is associated with a lower risk of sedation compared to other benzodiazepines and has high GABA-A receptor affinity 3
• In rat studies, oxazepam at therapeutic doses combined with buprenorphine showed only mild effects on sedation without significant respiratory depression at pharmacological doses 4
• Lorazepam's intermediate half-life and predictable metabolism (glucuronidation without active metabolites) may offer more controlled effects 3

Higher-Risk Options to Avoid

Avoid high-potency, long-acting benzodiazepines:

• Clonazepam at elevated doses (30 mg/kg in rats) combined with buprenorphine significantly increased PaCO₂, indicating respiratory compromise 4
• Nordiazepam (active metabolite of diazepam) combined with buprenorphine decreased PaO₂ and deepened sedation 4
• Diazepam combined with buprenorphine/naloxone in naive rats significantly decreased respiratory frequency, tidal volume, and minute volume 5

Safer Alternative Strategies

Prioritize non-benzodiazepine alternatives for anxiety and insomnia management:

• Sedating antidepressants (trazodone, mirtazapine, doxepin) are recommended as first-line add-on therapy instead of benzodiazepines 2
• Cognitive behavioral therapy for insomnia (CBT-I) should be added to any pharmacologic regimen, as it improves sleep parameters with moderate-quality evidence 2
• These alternatives avoid the synergistic respiratory depression risk entirely 2

Essential Safety Monitoring if Combination is Unavoidable

If you must prescribe a benzodiazepine with Suboxone despite the warnings:

• Use extreme caution and prescribe only for patients receiving close clinical monitoring appropriate to their level of stability 1
• Check the prescription drug monitoring program (PDMP) for concurrent controlled medications 2
• Monitor for progressive sedation, which often precedes respiratory depression 6, 2
• Patients with limited cardiopulmonary reserve are more susceptible to respiratory depression and require heightened vigilance 6
• Use the lowest effective dose for the shortest duration possible (ideally less than 2-4 weeks) 3
• Avoid prescribing multiple refills early in treatment without appropriate follow-up visits 1

Critical Pitfalls to Avoid

• Never assume the combination is safe based on patient tolerance or previous use—fatalities have been attributed to high-dose buprenorphine with benzodiazepines 4
• Do not prescribe benzodiazepines concurrently with other CNS depressants (including alcohol), as this creates additive effects on psychomotor performance and respiratory depression 2
• Warn patients explicitly against concomitant self-administration or misuse of benzodiazepines 1
• If tapering is necessary, taper the benzodiazepine gradually (25% dose reduction every 1-2 weeks) as benzodiazepine withdrawal carries greater risks than discontinuing other sedatives 2