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. 2023 Aug 1;158(8):854-864.
doi: 10.1001/jamasurg.2023.2009.

Association of Intraoperative Opioid Administration With Postoperative Pain and Opioid Use

Laura A Santa Cruz Mercado  1   2   3 , Ran Liu  1   2 , Kishore M Bharadwaj  1   2 , Jasmine J Johnson  1   2 , Rodrigo Gutierrez  1   2 , Proloy Das  1   2 , Gustavo Balanza  1   2 , Hao Deng  1   2 , Akriti Pandit  1   2 , Tom A D Stone  1   2 , Teresa Macdonald  1   2 , Caroline Horgan  4 , Si Long Jenny Tou  1   2 , Timothy T Houle  1   2 , Edward A Bittner  1   2 , Patrick L Purdon  1   2
Affiliations

Association of Intraoperative Opioid Administration With Postoperative Pain and Opioid Use

Laura A Santa Cruz Mercado et al. JAMA Surg. .

Abstract

Importance: Opioids administered to treat postsurgical pain are a major contributor to the opioid crisis, leading to chronic use in a considerable proportion of patients. Initiatives promoting opioid-free or opioid-sparing modalities of perioperative pain management have led to reduced opioid administration in the operating room, but this reduction could have unforeseen detrimental effects in terms of postoperative pain outcomes, as the relationship between intraoperative opioid usage and later opioid requirements is not well understood.

Objective: To characterize the association between intraoperative opioid usage and postoperative pain and opioid requirements.

Design, setting, and participants: This retrospective cohort study evaluated electronic health record data from a quaternary care academic medical center (Massachusetts General Hospital) for adult patients who underwent noncardiac surgery with general anesthesia from April 2016 to March 2020. Patients who underwent cesarean surgery, received regional anesthesia, received opioids other than fentanyl or hydromorphone, were admitted to the intensive care unit, or who died intraoperatively were excluded. Statistical models were fitted on the propensity weighted data set to characterize the effect of intraoperative opioid exposures on primary and secondary outcomes. Data were analyzed from December 2021 to October 2022.

Exposures: Intraoperative fentanyl and intraoperative hydromorphone average effect site concentration estimated using pharmacokinetic/pharmacodynamic models.

Main outcomes and measures: The primary study outcomes were the maximal pain score during the postanesthesia care unit (PACU) stay and the cumulative opioid dose, quantified in morphine milligram equivalents (MME), administered during the PACU stay. Medium- and long-term outcomes associated with pain and opioid dependence were also evaluated.

Results: The study cohort included a total of 61 249 individuals undergoing surgery (mean [SD] age, 55.44 [17.08] years; 32 778 [53.5%] female). Increased intraoperative fentanyl and intraoperative hydromorphone were both associated with reduced maximum pain scores in the PACU. Both exposures were also associated with a reduced probability and reduced total dosage of opioid administration in the PACU. In particular, increased fentanyl administration was associated with lower frequency of uncontrolled pain; a decrease in new chronic pain diagnoses reported at 3 months; fewer opioid prescriptions at 30, 90, and 180 days; and decreased new persistent opioid use, without significant increases in adverse effects.

Conclusions and relevance: Contrary to prevailing trends, reduced opioid administration during surgery may have the unintended outcome of increasing postoperative pain and opioid consumption. Conversely, improvements in long-term outcomes might be achieved by optimizing opioid administration during surgery.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Santa Cruz Mercado, Mr Bharadwaj, Dr Balanza, and Dr Purdon are inventors on a pending patent related to nociception and analgesia monitoring. Dr Das reported grants from the National Institutes of Health during the conduct of the study. Dr Houle reported serving as statistical editor for the American Society of Anesthesiologists and the American Headache Society outside the submitted work. Dr Purdon reported grants from the National Institutes of Health and other from Massachusetts General Hospital where Dr Purdon holds the Nathaniel M. Sims Endowed Chair in Anesthesia Innovation and Bioengineering during the conduct of the study. In addition, Dr Purdon is a cofounder of PASCALL Systems, a startup company developing closed-loop physiological control for anesthesiology. Dr Purdon is an inventor on patents related to brain monitoring using the electroencephalogram, one of which is under nonexclusive license by Massachusetts General Hospital to Masimo Corporation. Dr Purdon receives institutionally distributed licensing royalties for this license. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Study Population
PACU indicates postanesthesia care unit; PCA, patient-controlled analgesia; PK/PD, pharmacokinetic/pharmacodynamic. aSome individuals met multiple exclusion criteria.
Figure 2.
Figure 2.. Population Distribution of Exposures and Primary Outcomes
A, Vertical dashed lines represent the EC50 and EC95 for intraoperative fentanyl based on Vuyk et al. MME indicates morphine milligram equivalent; PACU, postanesthesia care unit.
Figure 3.
Figure 3.. Adjusted Odds Ratios (aOR) for Primary and Secondary Outcomes
The forest plot represents adjusted odds ratios with confidence intervals for each outcome for intraoperative fentanyl and hydromorphone exposure. We calculated odds ratios by exponentiating model coefficients. For hierarchical models, both components are presented (binomial and log-normal). For Cox proportional hazards models, adjusted odds ratios for expected time to event are presented. MME indicates morphine milligram equivalent; PACU, postanesthesia care unit; PONV, postoperative nausea and vomiting. aSecondary outcomes that were evaluated only in the subset of inpatients. bWe computed hazard ratios by exponentiating coefficients of Cox proportional hazards models, which are ratios of rates of event occurrence to population baseline rates. Greater hazard rates predict shorter event occurrence times; for example, for a 1-SD increase in intraoperative fentanyl exposure, our model predicts a hazard ratio with a 95% CI from 1.04 to 1.10, indicating an increased rate of hospital discharge, and a shorter length of stay.
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