Benzodiazepines Should Generally Be Avoided with Suboxone Due to Life-Threatening Respiratory Depression Risk
The combination of benzodiazepines with Suboxone (buprenorphine/naloxone) carries a significant risk of profound sedation, respiratory depression, and death, and should be reserved only for patients where alternative treatment options are inadequate. 1 If benzodiazepines must be used with Suboxone, prescribe the lowest effective doses for the shortest duration possible, with close monitoring for respiratory depression. 1
Critical Safety Warnings
The FDA has issued a boxed warning specifically addressing this combination: 1
- Concomitant use of benzodiazepines and opioids (including partial agonists like buprenorphine) may result in profound sedation, respiratory depression, coma, and death 1
- Buprenorphine exhibits multiple drug-drug interactions that can result in QT-interval prolongation, serotonin syndrome, paralytic ileus, reduced analgesic effect, or precipitation of withdrawal symptoms 2
- The respiratory depressant effects are synergistic because benzodiazepines act at GABA-A receptors while opioids act at mu receptors—different sites that control respiration 1
Evidence of Harm from This Combination
Clinical Data
- In France, where high-dose buprenorphine has been widely used since 1996, several asphyxic deaths were reported among patients treated with buprenorphine, particularly when combined with benzodiazepines or when buprenorphine was misused intravenously 3
- From 2006-2012 in U.S. emergency departments, 2.7% of encounters that prescribed an opioid also prescribed a benzodiazepine, with significantly higher odds in patients with mental health diagnoses 4
- The rate of death due to benzodiazepine-opioid overdose is increasing nationally 4
Experimental Evidence
- Animal studies demonstrate that buprenorphine combined with benzodiazepines causes significantly greater respiratory depression than either agent alone 5, 6
- In naive rats, buprenorphine/naloxone combined with diazepam significantly decreased tidal volume, respiratory frequency, and minute ventilation 5
- High-dose buprenorphine combined with midazolam induced sustained respiratory acidosis in rats, while buprenorphine alone did not 6
- Unlike other opiates, respiratory depression from buprenorphine is not reliably responsive to naloxone 3
When Benzodiazepines May Be Considered (Limited Exceptions)
Absolute Indications
Benzodiazepines are the treatment of choice as monotherapy for alcohol or benzodiazepine withdrawal, even in patients taking Suboxone, as the risks of untreated withdrawal outweigh the risks of benzodiazepine use 7, 8
Relative Indications Requiring Extreme Caution
- Severe agitation or distress where the patient poses an immediate risk to themselves or others, and only after antipsychotics have failed 7, 8
- Panic disorder or severe anxiety disorders where non-benzodiazepine alternatives (SSRIs, SNRIs, buspirone, hydroxyzine) have been inadequate 1
If Benzodiazepines Must Be Used: Specific Recommendations
Choice of Benzodiazepine
No specific benzodiazepine is definitively safer than others when combined with Suboxone, but consider the following pharmacological principles:
- Lorazepam may be preferred for crisis situations due to intermediate duration and lack of active metabolites, but its elimination half-life is significantly increased in renal failure 7
- Clonazepam at pharmacological doses (5 mg/kg in rats) did not significantly alter blood gases when combined with buprenorphine, whereas higher doses (30 mg/kg) increased PaCO2 6
- Avoid long-acting benzodiazepines (diazepam, clonazepam for chronic use) as active metabolites accumulate with prolonged administration 7
Dosing Strategy
- Start with the lowest possible doses: lorazepam 0.25-0.5 mg, clonazepam 0.25-0.5 mg, or alprazolam 0.25 mg 7, 9
- Limit dosages and durations to the minimum required 1
- Use PRN (as-needed) dosing initially rather than scheduled dosing 8
- In elderly or frail patients, use even lower starting doses (e.g., lorazepam 0.25 mg instead of 0.5 mg) 7
Monitoring Requirements
Patients receiving this combination require close monitoring for: 1
- Respiratory depression (decreased respiratory rate, shallow breathing, oxygen desaturation)
- Profound sedation or altered mental status
- Paradoxical agitation
- Signs of oversedation that may progress to coma
Alternative Management Strategies (Preferred)
For Agitation or Delirium
For Anxiety Disorders
- SSRIs or SNRIs as first-line pharmacotherapy
- Buspirone for generalized anxiety
- Hydroxyzine for acute anxiety symptoms
- Cognitive-behavioral therapy
Critical Pitfalls to Avoid
Do not assume the "ceiling effect" of buprenorphine for respiratory depression protects against benzodiazepine combinations—this ceiling effect is overcome when benzodiazepines are added 3, 5
Do not use flumazenil routinely to reverse benzodiazepine effects in patients on Suboxone—flumazenil is associated with harm (seizures, dysrhythmias) in patients at increased risk, and it does not reverse buprenorphine's respiratory effects 2
Do not combine benzodiazepines with antipsychotics (particularly olanzapine) in patients on Suboxone—this triple combination carries extreme risk of oversedation, respiratory depression, and fatalities 7
Do not prescribe benzodiazepines to manage symptoms that may be related to buprenorphine itself (such as sedation or altered mental status), as this will worsen the clinical picture 7
Do not discharge patients on new benzodiazepine-Suboxone combinations without ensuring they understand the risks and have a plan for close follow-up 1
Documentation and Patient Education
- Document the specific indication for benzodiazepine use and why alternative treatments were inadequate 1
- Assess each patient's risk for abuse, misuse, and addiction before prescribing 1
- Counsel patients to avoid alcohol while taking this combination 1
- Warn patients about the risk of profound sedation and respiratory depression 1
- Provide written instructions about signs of respiratory depression requiring emergency care 1