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Patient Safety Tip of the Week

October 26, 2021

Opioid-Induced Respiratory Depression Costly in Fiscal as Well as Human Terms



We’ve done many columns on OIRD (opioid-induced respiratory depression), highlighting the human toll associated with this phenomenon. However, a recent study has also highlighted the fiscal toll associated with OIRD (Khanna 2021a).


We discussed the PRODIGY trial in our October 20, 2020 Patient Safety Tip of the Week “More on Post-operative Risks for Patients with OSA”.  PRODIGY was a prospective, observational trial of blinded continuous capnography and oximetry conducted at 16 sites in the United States, Europe, and Asia aimed at prediction of opioid-induced respiratory depression on inpatient wards (Khanna 2020). Over 1300 patients on general care floors were receiving parenteral opioids (note: patients enrolled in the US were non-surgical patients and those enrolled elsewhere were postsurgical).


46% had one or more episodes of respiratory depression. Patients with ≥1 episode of respiratory depression were 2.5 times more likely to require some rescue intervention, including activation of a rapid response team. They also experienced 3 days longer mean hospital length of stay, which adds to costs.


A prediction model was developed using 5 independent variables: age ≥60 (in decades), sex, opioid naivety, sleep disorders, and chronic heart failure. The resultant PRODIGY score accurately predicted 74% of patients who would have episodes of respiratory depression and allowed separation of 3 groups (low-, medium-, and high-risk). Patients in the high-risk group by PRODIGY score were >6 times more likely to experience OIRD than the patients in the low-risk group.


The authors suggest that implementation of the PRODIGY score could determine the need for continuous monitoring and may be a first step to reduce the incidence and consequences of respiratory compromise in patients receiving opioids on the general care floor. This could certainly be welcome in those facilities that are resource-poor and cannot afford to do universal continuous monitoring with these modalities.


Patients in PRODIGY who had a respiratory depression (RD) episode often had multiple episodes. Khanna et al. did a secondary analysis of 250 patients from two of the PRODIGY participating centers to better understand these multiple episodes (Khanna 2021b), confirming that RD episodes were rarely isolated. One hundred and fifty-five patients had an RD episode, and of these 136 (88%) had multiple episodes. The number of RD episodes per patient increased with higher PRODIGY scores. The time from end of surgery to RD episode was also analyzed. The time to the first RD episode was 8.8 hours postoperatively with a peak occurrence of first RD episodes between 14:00–20:00 the day of surgery. Many subsequent episodes also occurred during this time, but there was a peak of RD occurrences the next morning from 02:00–06:00. The results suggested that the PRODIGY score not only calculates risk for a patient having an RD episode, but that these patients have more episodes. And the time distribution of RD episodes has important implications for postoperative continuous monitoring—specifically, such monitors should be applied upon dismissal from the recovery area.


A couple other interesting observations were seen in another post hoc analysis. Opioid use was significantly higher in the United States and Europe, compared to Asia. And there were differences by opioid type. 54% of patients who received only short-acting opioids (e.g., fentanyl) experienced ≥1 OIRD episode, whereas 45% who only received long-acting opioids experienced OIRD. Another interesting finding was that tramadol and epidural opioids were associated with a significant decrease in OIRD.


The most recent analysis of the PRODIGY data (Khanna 2021a) showed that respiratory depression on the general care floor is associated with a significantly longer length of stay and increased hospital costs. Patients with ≥1 respiratory depression episode had a longer length of stay compared to patients without respiratory depression. (mean LOS 6.4 days vs. 5.0 days, p = 0.009) and higher hospital cost ($21,892 vs. $18,206, p = 0.002). Propensity weighted analysis identified 17% higher costs for patients with ≥1 respiratory depression episode ($25,057 vs. $18,608, p = 0.007). Length of stay significantly increased total cost, with cost increasing exponentially for patients with ≥1 respiratory depression episode as length of stay increased.


Patient characteristics that significantly impacted length of stay and cost included use of multiple opioids; longer, high risk, or open surgery; respiratory depression; and medical conditions including chronic heart failure, hypertension, and sepsis.


The results of this analysis have potentially important implications. Many hospitals have been reluctant to implement universal continuous monitoring (with capnography and oximetry) in patients receiving opioids on general floors. Any savings from reduction of length of stay could potentially offset the costs of such monitoring. Khanna et al. suggest that future studies should explore whether early institution of these continuous monitoring measures, in combination with early proactive intervention, such as readjustment of analgesia, optimal fluid balance, aggressive incentive spirometry, and additional bronchodilation, mitigate the occurrence of respiratory depression and decrease hospital costs associated with such episodes.


Use of the PRODIGY score may help select patients who will benefit most from continuous monitoring, but it may well turn out that universal monitoring of patients receiving opioids may make sense from both a human and financial perspective.



As an aside, since we mentioned tramadol, there were 2 pertinent developments regarding tramadol recently. The FDA approved a combination pill, containing celecoxib and tramadol, for the treatment of adults with acute pain severe enough to require an opioid analgesic and for which alternative treatments fail to provide adequate pain relief (Brooks 2021). The same week, a study from Spain was published in JAMA showing that tramadol, compared with codeine, was significantly associated with a higher risk of subsequent all-cause mortality, cardiovascular events, and fractures (Xie 2021). An editorial accompanying that study (Kim 2021) cautions that the greatest risk of tramadol may involve the perception that tramadol is inherently safer than other opioids. We echo that point. Tramadol is an opioid and the potential effects of any opioid should be considered when prescribing it. You’ll recall our May 2017 What's New in the Patient Safety World column “FDA Finally Restricts Codeine in Kids; Tramadol, Too” added a contraindication to tramadol, stating that it should not be used to treat pain in children younger than 12 years and should not be used to treat pain in children younger than 18 years after a tonsillectomy and/or adenoidectomy.




Other Patient Safety Tips of the Week pertaining to opioid-induced respiratory depression and PCA safety:









Khanna AK, Saager L, Bergese SD. et al. Opioid-induced respiratory depression increases hospital costs and length of stay in patients recovering on the general care floor. BMC Anesthesiol 2021; 21: 88



Khanna AK, Bergese SD, Jungquist CR, et al. Prediction of opioid-induced respiratory depression on inpatient wards using continuous capnography and oximetry: an international prospective, observational trial. Anesth Analg 2020; 131(4): 1012-1024



Khanna AK, Urman RD, Weingarten TN. One Year After PRODIGY—Do We Know More About Opioid-Induced Respiratory Depression? APSF Newsletter 2021; 36(2):



Xie J, Strauss VY, Martinez-Laguna D, et al. Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes. JAMA 2021; 326(15): 1504-1515



Kim HS, McCarthy DM, Lank PM. Tramadol, Codeine, and Risk of Adverse Outcomes. JAMA 2021; 326(15): 1483-1484



Brooks M. FDA Approves Combo Pill for Severe, Acute Pain. Medscape Medical News 2021; October 19, 2021





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