Sex-Based Differences in Opioid-Induced Respiratory Depression

Background 

The opioid epidemic is one of the largest public health crises the United States has faced in recent years. From 1999 to 2011, the rate of opioid-related overdose deaths nearly quadrupled and the rate of individuals seeking treatment for opioid addiction increased by almost 900% ^1,2. In 2014, the United States Centers for Disease Control and Prevention added opioid overdose prevention to its list of top five public health challenges to address in the coming years ². Today, the treatment and management of opioid use disorders remains a major challenge across medical specialties. With over 70,000 opioid-related deaths reported in the United States in 2017, health care providers must continue to work together to prevent and treat opioid use disorders ³.

Adverse Effects of Opioid Use: Opioid-Induced Respiratory Depression (OIRD)

Overdose-associated death is not the only adverse public health outcome tied to opioid agonist medication use ². In addition to general opioid adverse effects such as constipation, nausea, drowsiness and delirium, the accumulation of opioids or active metabolites can lead to serious outcomes such as OIRD ⁴. OIRD is a life-threatening condition and can result in respiratory or cardiopulmonary arrest if left untreated ⁵.

Risk factors for OIRD 

Both medical and surgical patients taking opioids are at risk of developing OIRD in a hospital setting ⁴. Somnolence and sedation are the most frequently reported precursors leading to OIRD, and regular monitoring by nursing staff is currently the primary method for tracking such conditions ⁶. There are a wide range of groups with a particularly elevated risk of developing OIRD, including: morbidly obese patients, patients with sleep apnea, patients with neuromuscular disease, premature infants, pediatric patients suffering from breathing problems during sleep, elderly patients and critically ill patients ⁷.

Sex differences in OIRD: Do they exist? 

Past studies looking at sex-based differences in OIRD often focus on morphine use. In 1998, Dahan et al. conducted a placebo-controlled, double-blind randomized study investigating the interaction of sex differences and morphine on ventilatory control. Researchers found that morphine had a significant effect on ventilatory oxygen and carbon dioxide responsiveness in women; however, no significant difference in these parameters was found in men ⁸.

A follow-up study conducted in 2000 compared the effects of morphine analgesia on a group of 20 healthy volunteers (10 males, 10 females) by measuring pain threshold and pain tolerance. Researchers found that morphine had a greater potency in women, even though women experienced a slower onset and offset of analgesia compared to men. Researchers concluded that the study results are consistent with their previous findings on sex-related differences in the ventilatory effects of morphine and may explain why men consume more opioids than women in a post-operative setting. ⁹

In 2014, Overdyk et al. reviewed a collection of case reports involving OIRD in different acute care settings. The authors found that the most frequently reported case-related factor for OIRD was morphine and the most frequently reported patient-related factor was female gender. ¹⁰

Conclusions: Where to go from here? 

While sex-specific differences in morphine-related OIRD are clinically important, there are two major areas where current literature is lacking. First, few researchers have investigated the influence of sex on OIRD in patients with substance use disorders (SUD). The opioid epidemic is creating a population of patients with SUD. As a result, there is a need to better understand OIRD, particularly in emergency settings across the United States. Second, few studies have been published on sex-specific differences in OIRD with the administration of opioids other than morphine. In order to better counsel patients and provide sex-specific treatment of opioid addiction, research is needed to determine if OIRD differs between men and women with SUD.

References

1. Rudd, R. A., et al. (2016). "Increases in Drug and Opioid Overdose Deaths--United States, 2000-2014." MMWR: Morbidity and Mortality Weekly Report 64(50-51): 1378-1382.
2. Kolodny, A., et al. (2015). "The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction." Annual Review of Public Health 36: 559-574.
3. Colon-Berezin, C., et al. (2019). "Overdose Deaths Involving Fentanyl and Fentanyl Analogs - New York City, 2000-2017." MMWR: Morbidity and Mortality Weekly Report 68(2): 37-40.
4. Suga, Y., et al. (2019). "Current Status of Adverse Events Related with Opioid Analgesics in Japan: Assessment Based on Japanese Adverse Drug Event Report Database." Biological and Pharmaceutical Bulletin 42(5): 801-806.
5. Izrailtyan, I., et al. (2018). "Risk factors for cardiopulmonary and respiratory arrest in medical and surgical hospital patients on opioid analgesics and sedatives." PloS One 13(3): e0194553.
6. Pasero, C. and M. McCaffery (2002). "Monitoring Sedation: It's the key to preventing opioid-induced respiratory depression." AJN The American Journal of Nursing 102(2): 67-69.
7. Brant, J. M., et al. (2018). "Predictors of oversedation in hospitalized patients." American Journal of Health-System Pharmacy 75(18): 1378-1385.
8. Dahan, A., et al. (1998). "Sex-related differences in the influence of morphine on ventilatory control in humans." Anesthesiology 88(4): 903-913.
9. Sarton, E., et al. (2000). "Sex differences in morphine analgesia: an experimental study in healthy volunteers." Anesthesiology 93(5): 1245-1254; discussion 1246A.
10. Overdyk, F., et al. (2014). "Opioid-induced respiratory depression in the acute care setting: a compendium of case reports." Pain Manag 4(4): 317-325.

Lindsay Walsh
University of Massachusetts Medical School