Is it safe to use Xanax (alprazolam) with acetaminophen-codeine?

Safety of Combining Xanax (Alprazolam) with Acetaminophen-Codeine

Xanax (alprazolam) should not be used concurrently with acetaminophen-codeine due to the significant risk of respiratory depression and potentially fatal overdose from combining benzodiazepines with opioids. 1

Risks of Concurrent Use

• Benzodiazepines (like Xanax) and opioids (like codeine) both cause central nervous system depression and can decrease respiratory drive, putting patients at greater risk for potentially fatal overdose 1
• Epidemiologic studies show concurrent benzodiazepine use in a large proportion of opioid-related overdose deaths 1
• A case-cohort study found concurrent benzodiazepine prescription with opioid prescription was associated with a nearly quadrupled risk for overdose death compared with opioid prescription alone 1

Pharmacological Considerations

• Codeine is a prodrug that is hepatically metabolized to morphine and other metabolites primarily through the cytochrome P450 enzyme CYP2D6 1
• Alprazolam (Xanax) may interact with other medications through the cytochrome P450 system, potentially affecting drug metabolism 1
• The combination of central nervous system depressants can potentiate the sedative effects of each drug, increasing risk of adverse outcomes 1

Special Considerations

• If there are circumstances when it might be appropriate to prescribe opioids to a patient receiving benzodiazepines (e.g., severe acute pain in a patient taking long-term, stable low-dose benzodiazepine therapy), this should only be done with extreme caution and close monitoring 1
• When patients are receiving both benzodiazepines and opioids and require tapering to reduce risk for fatal respiratory depression, it might be safer and more practical to taper opioids first 1

Management Recommendations

• Check prescription drug monitoring programs for concurrent controlled medications prescribed by other clinicians 1
• Consider involving pharmacists and pain specialists as part of the management team when opioids are co-prescribed with other central nervous system depressants 1
• If pain management is required for a patient on benzodiazepines, consider non-opioid analgesics such as NSAIDs or acetaminophen alone (without codeine) 1
• For patients requiring treatment of anxiety who are on opioids, evidence-based psychotherapies (e.g., CBT) and/or specific antidepressants or other non-benzodiazepine medications approved for anxiety should be offered instead of benzodiazepines 1

Acetaminophen-Codeine Specific Concerns

• Acetaminophen-codeine is a combination product that carries risks related to both components 1
• Acetaminophen can cause hepatotoxicity when used improperly or in excessive doses 1
• Codeine's analgesic effect varies between individuals due to CYP2D6 polymorphism - some patients may be poor metabolizers with reduced analgesic effects, while rapid metabolizers may experience toxicity 1

Alternative Approaches

• For pain management, consider non-opioid analgesics such as NSAIDs or acetaminophen alone 1
• For anxiety management in patients requiring pain control with opioids, consider non-benzodiazepine anxiolytics or evidence-based psychotherapies 1
• If both medications are deemed absolutely necessary, involve specialists in pain management and psychiatry to coordinate care and closely monitor the patient 1