Compared to patients in the low opioid dose group, those in the high opioid dose group had approx. 50% increased odds for DVT and postoperative infections (OR 1.53 [CI 1.39-1.69], OR 1.49 [1.24-1.78], P < 0.001, respectively), while odds for PE were increased by about 28% (OR 1.28 [1.15-1.42], P < 0.001). Furthermore, opioid prescription in the highest quartile was associated with significantly increased odds by about 20% for gastrointestinal and urinary complications (OR 1.20 [1.15-1.26], OR 1.23 [OR 1.18-1.29]), while risk was increased by approx. 15% for respiratory complications and bradycardia (OR 1.15 [1.10-1.21], OR 1.15 [1.07-1.25]); P < 0.001, respectively. The risk for myocardial infarction remained unaltered by opioid dose; however, odds for cerebrovascular complications were decreased by about 25% in high opioid prescription (OR 0.75 [CI 0.61-0.91], P = 0.004). In terms of resource utilization, analysis showed that LOS was significantly increased by about 12% and cost by about 6% in high vs low opioid prescription among cases of joint replacement. Dichotomized analysis revealed that in high opioid prescription, odds for prolonged LOS and increased cost, defined as LOS and cost above the 75% percentile, were increased by 76% and 40%, respectively (P < 0.001).
In patients with spine fusions, baseline opioid prescription was significantly higher and most outcomes followed a similar trend. Notably, LOS was significantly increased by 22%, while cost significantly increased by about 14% in patients with high vs low opioid prescription. Furthermore, in high opioid prescription the risk for prolonged LOS and increased cost, was increased by 84% and 76%, respectively (P < 0.001). Consistently, high opioid prescription was associated with significantly increased odds by more than 30% for gastrointestinal and urinary complications when opioids were prescribed in higher dosage. Other outcomes followed a similar trend, however, without statistical significance, possibly because of the substantially lower sample size of this cohort.
This observational study of 1,256,531 major orthopedic surgeries investigated postoperative complications as a function of opioid dosage. High opioid prescription was associated with increased adjusted odds for numerous postoperative complications and resource utilization. The strongest effect was observed in increased odds for thromboembolic, infectious, and gastrointestinal complications as well as increased LOS and cost. Notably, these changes in odds mostly occurred in a stepwise manner with significantly rising odds for adverse outcome from low to medium and further to high opioid prescription dose. This observed dose–response gradient, is a factor established as raising the quality of evidence.15 Spine patients had higher opioid prescription from baseline, and effects for gastrointestinal and urinary complications and the continuous outcomes LOS and cost were more pronounced compared to TJAs, while other outcomes did not reach statistical significance, possibly because of the substantially lower sample size. Higher opioid dosage was associated with decreased odds for cerebrovascular accident in TJAs, potentially indicating a neuroprotective opioid-related effect.
4.1. Cardiac complications
Overall, analysis showed that odds for myocardial infarction remained unaltered by increase in opioid dose, while a decrease by trend between medium and low opioid dose was observed in spine cases.
Given scientific evidence from in vivo and vitro animal and human trials on the impact of opioids on cardiac muscle function, opioids could possibly confer a direct cardio protective effect.34 Studies suggest that opioid receptor stimulation can enable myocardial adaption to transient ischemia with reduced myocardial injury by a mechanism named preconditioning.13,28 Moreover, naloxone appears to revers opioid-mediated cardioprotection.27,35,39
Besides direct cardioprotection, opioids can decrease the sympathetic tone and enhance vagal activity, resulting in decreased workload and oxygen consumption, thus recommended in acute myocardial infarction.2,8,38 In this respect, the current analysis demonstrates a significant association between higher opioid prescription and increased odds for bradycardia, while risk for myocardial infarction did not increase by opioid dose. Nevertheless, while these data cannot establish causal conclusions, results are in line with evidence supporting opioid-related cardioprotection, a notion currently considered in cardiac pharmacological drug design.32,42
4.2. Respiratory complications
Analysis showed an increase in odds for respiratory complications in high vs low opioid dose. Respiratory depression is mediated by μ2-opioid receptors in the brainstem, and characterized by a dose-dependent decline in minute volume, with decreased respiratory rate, while opioid-mediated airway obstruction due to reduced pharyngeal muscle tone can aggravate respiratory compromise.3 Opioids are mainly feared for their propensity to induce respiratory failure; however, hesitant use can compromise adequate pain management.1
4.3. Urinary complications
Higher opioid prescription was associated with significantly increased odds for urinary retention. Notably, this effect appeared stepwise in terms of a dose–response relationship in both patient cohorts. Postoperative urinary retention is common after orthopedic surgery, with drivers including, age, comorbidities, and anesthesia technique.4 The addition of opioids as part of regional anesthesia has been suggested to potentially increase urinary retention.4,12
4.4. Thromboembolic complications
In TJAs, high vs low opioid dose was associated with significantly increased odds by more than 50% for DVT and about 30% for PE. A link between morphine, platelet activity, and coagulation has been suggested, as experimental trials have demonstrated that morphine antagonized prostaglandin E1-mediated inhibition of platelet aggregation, thus reducing the protective effect of prostaglandin.14 Furthermore, opioid sparing could potentially act preventive by promoting postoperative mobilization.19 Although this analysis cannot confer casual conclusions, results are consistent with previous evidence, suggesting a stepwise dose-dependent association between opioid prescription and thromboembolic complications from low to medium and high opioid dose.20 Interestingly, the centers of Medicare and Medicaid services added these outcomes to hospital acquired conditions, affecting reimbursement.5
The lack of significant opioid dose–related effects in spine patients for some outcomes including thromboembolic complications, is likely due to the substantially lower sample size.
4.5. Cerebrovascular accident
In TJAs, higher opioid dose was associated with decreased odds for cerebrovascular accident by 25% (P < 0.004). While a reduction in stroke rate in the highest opioid quartile could be linked to reduced sympathetic tone with reduced blood pressure spikes, it should be mentioned that a growing body of preclinical scientific evidence also suggests the existence of direct opioid-related neuroprotection.16,40 Opioid receptors are prevalent throughout the central and peripheral nervous system and experimental stroke models indicate that opioid receptor activation can positively affect ischemic outcome by cellular pathways with reduced edema and infarction ratios as well as neurological improvement.40 Moreover, naloxone appears to revers opioid-related neuroprotection.41 While the current analysis cannot verify previous scientific suggestions, results are in support on a population-based level.
4.6. Postoperative infection
High opioid dose was associated with significantly increased adjusted odds for infections by over 50% in TJAs.
A potential link between opioid analgesia and the occurrence of infections has recently emerged as an important health care concern. Experimental research, including in vitro human studies, has been at the forefront of demonstrating opioid-induced immune suppression on a humoral and cell-mediated level with increased susceptibility to infections.6,36,37 Furthermore, clinical studies have demonstrated dose-dependent associations between opioid utilization and postoperative infectious complications in cardiac surgery11 and treatment of burn patients.33 Again, while no causality can be conferred, this population-based analysis supports the notion of a dose-dependent relationship between opioid use and postoperative infections.
4.7. Length of stay and cost of hospitalization
Analysis showed a stepwise increase in LOS and cost from low to medium and further to high opioid prescription in both patient populations. As such high levels of opioid prescription were associated with an increase in LOS by 12% in joint replacements, while an increase of 22% for LOS was observed in spine patients, who received significantly higher opioid amounts. Similarly cost increased by 6% in joint replacements and 14% in spine fusions with high levels of opioid prescription. Dichotomized analysis of these outcomes showed that the odds for prolonged LOS, defined as LOS above the 75th percentile, were increased by approx. 80% when opioid were prescribed at a high dose level in both patient cohorts. Consistently, the odds for increased cost, defined as cost beyond the 75th percentile, were increased by 40% in joint replacements and 76% in spine patients, when high opioid dosage was prescribed. Longer LOS and higher cost may potentially be a marker of increased difficulty to control pain on the one hand and higher complication rates requiring additional treatment on the other.
Several limitations should be mentioned. Our data do not allow conclusions regarding causality of the observed associations, which require cautious interpretation using plausibility. Data were primarily collected for billing purposes, therefore, the lack of clinical detail, limiting the depth to which analysis was feasible.
Analysis was performed with respect to in-hospital opioid prescription, rather than actual use, because of the absence of information on the latter. Nevertheless, opioid prescription was investigated only within 48 hours postoperatively, thus likely closely linked to actual use. Importantly, the association between opioid prescription doses and outcomes, points to an important indicator in need of consideration, particularly given initiatives for opioid sparing approaches from a policy point of view. Other limitations relate to the lack of data regarding pain severity or control and rehabilitation, which are potential drivers in the occurrence or lack of opioid-related effects and complications. For instance, a finding of low pain scores in high opioid dose would strengthen our results, while high pain scores might rather indicate increased severity of surgical trauma. However, besides adjustment for comorbidities and other baseline variables, adjustment for preoperative pain conditions and a history of preoperative substance use or abuse was performed, to limit potential risk of bias introduced by these conditions. Nonetheless, this analysis could not capture all drivers of opioid prescription. In this context, the influence of unmeasured variables such as pain severity and mobilization milestones cannot be excluded as residual confounders. Finally, while differences in coding practice and sporadic coding errors cannot be excluded as a source of bias, resulting impact on analysis should be limited as the focus was on the incidence related to opioid dose and comparative in nature. Moreover, these errors are likely evenly distributed, further limiting resulting bias.
Overall, perioperative opioid utilization and potential harm remain a significant concern on a public health care level. Although opioid sparing has become a priority, evidence demonstrating a direct association between opioid dosage and postoperative outcomes is largely lacking. This analysis demonstrates that higher opioid dose is indeed associated with increased risk for respiratory, gastrointestinal, urinary, thromboembolic, and infectious complications, as well as increased cost and LOS. Notably, the incidence of many postoperative complications increased in a stepwise manner from low to medium and high opioid dosing, suggesting a dose–response gradient. The impact on complication odds, however, may not be uniform, as opioids may lack detriment or potentially confer protective effects on a cerebrovascular and cardiac level. Moreover, findings are in line with current scientific mechanistic evidence, providing a basis for policy makers and formal hypothesis testing in clinical trials targeting balance between analgesia and potential harm.
Conflict of interest statement
A. P. Hughes reports other from MiMedx Group, Inc, grants from NuVasive, Inc, personal fees from Altus Spine LLC, outside the submitted work. The others authors have no conflict of interest to declare.
Funding: This work accomplished by institutional funding. Furthermore, Dr S. G. Memtsoudis is funded by the Anna Maria and Stephen Kellen Career Development Award, New York, NY. The sponsors had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, nor in preparation, review, and approval of the manuscript. C. Cozowicz helped design the study, conduct the study, analyze the data, and write the manuscript. A. Olson helped design the study, conduct the study, analyze the data, and write the manuscript. J. Poeran helped design the study, conduct the study, analyze the data, and write the manuscript. E. E. Mörwald helped design the study, conduct the study, analyze the data, and write the manuscript. F. P. Girardi helped design the study, conduct the study, analyze the data, and write the manuscript. A. P. Hughes helped design the study, conduct the study, analyze the data, and write the manuscript. M. Mazumdar helped design the study, conduct the study, analyze the data, and write the manuscript. S. G. Memtsoudis helped design the study, conduct the study, analyze the data, write the manuscript, and S. G. Memtsoudis attests to the integrity of the original data and has approved the final manuscript. Institutional Review boards, that approved the study: Institutional Review Board of the Hospital for Special Surgery 535 East 71st Street, New York, 10021 NY, USA (#2012-050-CR2). Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA (#14-00647). Data sharing: Data was purchased from Premier and is restricted for this project and cannot be shared because of these restrictions on use of data. Syntax is available from the corresponding author (firstname.lastname@example.org). Transparency: The senior author, S. G. Memtsoudis affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
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Postoperative complications; Opioid prescription; Orthopedic surgery; Opioid dose; Postoperative outcome; Arthroplasty; Postoperative outcome
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