What are the effects and risks of taking buprenorphine (Subutex) together with clonazepam (Klonopin)?

Dangerous Combination: Severe Respiratory Depression and Death Risk

Taking Subutex (buprenorphine) and Klonopin (clonazepam) together creates a life-threatening risk of respiratory depression, loss of consciousness, and death. 1, 2

Critical Safety Warning

The FDA has issued a black box warning specifically about this combination, stating that concomitant use of benzodiazepines (like Klonopin) with opioids (including buprenorphine) increases the risk of respiratory depression because they act at different receptor sites in the CNS that control respiration—benzodiazepines at GABA-A sites and opioids at mu receptors. 3, 2

• Potentially fatal additive effects occur when these drugs are combined, with documented cases of death from this specific interaction. 2, 4
• The combination produces profound and prolonged respiratory depression with rapid onset, leading to severe increases in carbon dioxide levels (respiratory acidosis) and delayed oxygen deprivation. 5, 6
• A fatal case report documented a 38-year-old woman who died from combined oxycodone (similar opioid) and clonazepam toxicity, with autopsy findings showing collapsed lungs, aspirated mucus, and heart failure from severe CNS and respiratory depression. 4

Specific Physiological Effects

The drugs work synergistically through different mechanisms to produce more severe effects than either alone:

• Buprenorphine alone causes only mild, transient effects on blood pH and carbon dioxide levels at therapeutic doses. 5
• Clonazepam alone similarly produces mild effects on respiratory parameters. 5
• When combined, they produce rapid, profound, and prolonged respiratory depression with severe respiratory acidosis (pH dropping to 7.25) and delayed hypoxia appearing within 2 hours. 6
• The combination significantly deepens sedation beyond either drug alone, even at pharmacological doses. 5

Clinical Presentation of Toxicity

Patients taking this combination are at risk for:

• Severe drowsiness and loss of consciousness 1, 2
• Slowed or difficult breathing progressing to respiratory arrest 3, 1
• Profound sedation and inability to be aroused 2
• Hypotension and cardiovascular collapse 4
• Death, particularly when combined with other sedating substances 1, 2

Special Considerations for Opioid Use Disorder Treatment

In pregnant women with opioid use disorder requiring buprenorphine maintenance:

• Methadone may be more appropriate than buprenorphine if there is concurrent benzodiazepine use. 3
• However, buprenorphine should not be withheld from women concurrently using benzodiazepines if it is the only accessible or preferred pharmacotherapy—the FDA instead recommends careful medication management rather than withholding treatment. 3
• This reflects the critical importance of maintaining opioid use disorder treatment to prevent relapse to more dangerous illicit opioids. 3

Management Approach

If a patient is taking both medications:

• Limit dosage and duration of concomitant use and follow patients closely for respiratory depression and sedation. 2
• Monitor for progressive sedation, which often precedes respiratory depression. 3
• Consider tapering the benzodiazepine first rather than the buprenorphine, as benzodiazepine withdrawal carries greater risks than opioid withdrawal, and tapering opioids can be associated with anxiety. 3
• Use a gradual benzodiazepine taper (25% dose reduction every 1-2 weeks) to avoid withdrawal complications including seizures and delirium tremens. 3
• Provide naloxone to caregivers for emergency use if respiratory depression occurs. 3

Common Pitfalls to Avoid

• Do not assume the combination is safe at prescribed doses—fatalities have occurred even with therapeutic dosing. 4
• Do not dismiss increasing drowsiness as a benign side effect—progressive sedation signals impending respiratory failure. 3
• Do not abruptly discontinue either medication without medical supervision, as both can cause dangerous withdrawal syndromes. 1, 2
• Do not add alcohol or other sedating medications (antihistamines, sleep aids, muscle relaxants) to this already dangerous combination. 1, 2