What factors increase the risk for opioid overdose?


Opioids are potent analgesics prescribed for acute and chronic pain.1 They exert their pharmacological effects by binding to the opioid receptors (delta, kappa, mu) found throughout the central nervous system (CNS), primarily the mu receptors.2 Opioid overdose, in which an excessive amount of a dose is given, can cause opioid toxicity leading to CNS depression and reduction in the respiratory drive. This can be life-threatening and fatal. The Centers for Disease Control and Prevention (CDC) reported that 165,000 people died of an opioid overdose in the United States in the 15-year period spanning from 1999 to 2014.1


In 2016, the CDC published a guideline to provide primary care providers with recommendations for opioid prescribing in chronic pain.1 One recommendation advises clinicians to evaluate risk factors for opioid-related harms before initiating or continuing opioid therapy. The following factors increase the risk for opioid overdose:

  1. History of overdose
    History of an overdose increases the risk for future opioid overdose by a factor of 6.1,3
  2. History of substance use disorder
    History of substance use disorder may lead to opioid misuse.1 Patients with drug or alcohol use disorder have a higher risk for opioid overdose.
  3. Higher opioid dosages (greater than or equal to 50 morphine milligram equivalents (MME)/day)
    Higher opioid dosages increase the risk for opioid overdose risk.1 Clinical evidence found that compared to dosages of 1 to 20 MME/day, doses of 50 to 100 MME/day and those greater than 100 MME/day increased the risk for opioid overdose by 1.9 to 4.6 times and 2.0 to 8.9 times, respectively.
  4. Concurrent use of a benzodiazepine
    Like opioids, benzodiazepines can cause CNS depression and decrease respiratory drive.1 The concurrent use of benzodiazepines with opioids has an additive effect, which increases the risk of a fatal overdose. Patients who use benzodiazepines and opioids concurrently have almost 4 times higher risk for a fatal overdose compared with patients who use opioids alone.
  5. Sleep-disordered sleeping
    Opioids should be avoided in patients with moderate or severe sleep-disordered breathing.1
  6. Renal or hepatic insufficiency
    Patients with renal or hepatic insufficiency metabolize and eliminate drugs at a lower capacity.1 As a result, opioids and opioid by-products accumulate in the body, increasing the risk for an overdose.


  1. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. MMWR Recomm Rep. 2016;65(1);1-49. Published March 15, 2016. https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm . Accessed December 26, 2019
  2. Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012;6(1):11-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590096/pdf/10.1177_2049463712438493.pd. Accessed December 26, 2019.
  3. Preventing fatal opioid overdose among your patients. Prescribe to prevent.org. https://prescribetoprevent.org/wp2015/wp-content/uploads/GeneralProvider_Brochure.TCG-Rx-to-save-a-life.pdf. Accessed November 21, 2019.

Prepared by:
Khoa Le, PharmD
Clinical Instructor
University of Illinois at Chicago College of Pharmacy

The information presented is current as of December 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.