Prescribing opioids alongside antipsychotics: understanding the risks 

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More than half of opioid prescriptions in the United States are filled by patients with comorbid mental health disorders, including patients who are using antipsychotics. Compared to the general population, patients with severe mental illness are 2.5 times more likely to be treated with opioids for chronic pain. It’s important that providers take precautions when prescribing opioids to patients using antipsychotics, as concurrent use of these drug classes can result in excessive drowsiness, respiratory depression, overdose and death.

Legislative action 

In 2016, the US Food and Drug Administration (FDA) issued a black-box warning about combining opioids and antipsychotics due to risks of respiratory depression. In 2018, the United States Congress passed the SUPPORT for Patients and Communities Act to promote opioid use disorder prevention, recovery, and treatment.  

Antipsychotics with higher risks of overdose 

When taken with opioids, sedating antipsychotics are associated with an increased risk (up to 60%) of unintended overdose compared to nonsedating antipsychotics. Broadly speaking, antipsychotics can be classified as sedating (e.g., chlorpromazine, clozapine, olanzapine and quetiapine) and less or nonsedating (e.g., aripiprazole, haloperidol, lurasidone, risperidone and ziprasidone) based on histamine-1 receptor affinity (Ki < or ≥20, respectively). 

Ways to protect patients 

Please consider the following precautions when prescribing opioids to patients taking antipsychotics.  

  • Limit prescribing opioid pain medications with sedating antipsychotics to patients for whom alternative treatment options are inadequate. 
  • If concurrent use is necessary, reduce initial dosage of opioid and titrate to clinical response. Use the lowest effective doses and minimum treatment durations. 
  • Monitor patients for serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Taking opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. 
  • Avoid prescribing opioid cough medication to patients taking olanzapine. 
  • Consider prescribing naloxone (Narcan) when prescribing an opioid.  

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