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Opioid prescription levels and postoperative outcomes in orthopedic surgery

Cozowicz, Crispianaa,b; Olson, Ashleyc; Poeran, Jashvantc; Mörwald, Eva E.a,b; Zubizarreta, Nicolec; Girardi, Federico P.d; Hughes, Alexander P.d; Mazumdar, Madhuc; Memtsoudis, Stavros G.a,b,*

doi: 10.1097/j.pain.0000000000001047
Research Paper
Global Year 2017

Given the basic need for opioids in the perioperative setting, we investigated associations between opioid prescription levels and postoperative outcomes using population-based data of orthopedic surgery patients. We hypothesized that increased opioid amounts would be associated with higher risk for postoperative complications. Data were extracted from the national Premier Perspective database (2006-2013); N = 1,035,578 lower joint arthroplasties and N = 220,953 spine fusions. Multilevel multivariable logistic regression models measured associations between opioid dose prescription and postoperative outcomes, studied by quartile of dispensed opioid dose. Compared to the lowest quartile of opioid dosing, high opioid prescription was associated with significantly increased odds for deep venous thrombosis and postoperative infections by approx. 50%, while odds were increased by 23% for urinary and more than 15% for gastrointestinal and respiratory complications (P < 0.001 respectively). Furthermore, higher opioid prescription was associated with a significant increase in length of stay (LOS) and cost by 12% and 6%, P < 0.001 respectively. Cerebrovascular complications risk was decreased by 25% with higher opioid dose (P = 0.004), while odds for myocardial infarction remained unaltered. In spine cases, opioid prescription was generally higher, with stronger effects observed for increase in LOS and cost as well as gastrointestinal and urinary complications. Other outcomes were less pronounced, possibly because of smaller sample size. Overall, higher opioid prescription was associated with an increase in most postoperative complications with the strongest effect observed in thromboembolic, infectious and gastrointestinal complications, cost, and LOS. Increase in complication risk occurred stepwise, suggesting a dose–response gradient.

A stepwise opioid dose–dependent increase in numerous postoperative complications, cost, and length of stay was observed suggesting a dose–response gradient.

aDepartment of Anesthesiology, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA

bDepartment of Anesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medical University, Salzburg, Austria

cDepartment of Population Health Science and Policy, Institute for Healthcare Delivery Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

dDepartment of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA

Corresponding author. Address: Department of Anesthesiology, Hospital for Special Surgery, Department of Public Health, Weill Cornell Medical College, 535 East 70th St, New York, NY 10021, USA. Tel.: 212-606-1206; fax: 212-517-4481. E-mail address: (S. G. Memtsoudis).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received February 15, 2017

Received in revised form July 14, 2017

Accepted August 21, 2017

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1. Introduction

Opioids are essential elements of perioperative pain management, ultimately contributing to surgical success. However, detrimental side effects are a known and feared entity.17 In this context, the escalating use of therapeutic opioids over the past 2 decades has rendered clinical utilization a public health concern, with many calling for policies to reduce opioid prescriptions.18,21 This represents a specific challenge in the perioperative setting, as practitioners and policy makers aim to reconcile the commitment to provide efficient pain control,7,31 with the avoidance of opioid side effects. Trends indicating an increase in surgical volume likely aggravate this problem.17

Despite the fact that opioid side effects are well established,30 evidence demonstrating opioid dose–dependent perioperative outcomes on a population level is lacking. Paucity of such data hinders an evidence based approach to this issue. Therefore, we investigated the association between opioid prescription levels and postoperative outcomes using nationwide population-based data from over 1 million patients undergoing high volume surgeries, including total lower joint arthroplasties (TJAs) and spine fusions. Our goal was to explore a potentially underlying dose–response relationship between opioid prescriptions and postoperative outcomes, while we hypothesized that increased opioid amounts would be associated with higher odds for adverse outcome.

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2. Materials and methods

2.1. Data source

We used data collected between 2006 and 2013 from the Premier Perspective database (Available at Last accessed December 9, 2016), covering approximately 25% of US hospitals. Services provided were determined through the analysis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes, Current Procedural Terminology (CPT) codes, and standardized billing items. The study protocol was approved by the Institutional Review Boards of the Hospital for Special Surgery and the Icahn School of Medicine and was exempt from requirements for consent, as data is compliant with the Health Insurance Portability and Accountability Act.

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2.2. Analysis plan

An analysis plan was formed by the group before the start of this project. As such, we defined primary outcomes of interest (defined below) a priori to include postoperative outcomes associated with quartile of prescribed opioid dosage in patients undergoing primary hip and knee arthroplasties and spine fusions. Stratification by procedures of total joint arthroplasties and spine fusions was defined at the outset to account for differences in terms of invasiveness, pain intensity, and perioperative care. Subgroups of these data obtained from Premier Perspective have been used by our study group for previous analyses, including an initial descriptive evaluation of trends regarding the use of regional anesthesia,9 an analysis of potential differences in care,23 as well as to investigate the impact of regional anesthesia, including neuraxial24 and peripheral nerve blocks on outcomes.22

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2.3. Study sample

We included patient records with an (elective, primary) ICD-9 procedure code for total hip arthroplasty (81.51), knee arthroplasty (81.54), dorsal and dorsolumbar fusion (81.05), lumbar and lumbosacral fusion–lateral transverse process technique (81.07), and lumbar and lumbosacral fusion, posterior technique (81.08) from 2006 to 2013. Cases with unknown sex (n = 22), unknown discharge status (n = 1175), outpatient procedures (n = 9089), and multiple procedures during the hospital admission (n = 246) were excluded.

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2.4. Variables

We analyzed demographics, comorbidity burden (Deyo adaption of the Charlson comorbidity index),10 obesity, obstructive sleep apnea status, anesthesia technique, and hospital characteristics. Furthermore, we analyzed the occurrence of preoperative substance use or abuse and preoperative pain conditions. The primary effect variable of interest was opioid utilization, defined as perioperative in-hospital opioid prescription for the day of surgery and the day thereafter. Billing for various opioids was converted into oral morphine equivalents (using the Lexicomp [Available at Last accessed December 9, 2016] “opioid agonist conversion” and the GlobalRPH [Available at Last accessed December 9, 2016] “opioid analgesic converter”) and subsequently stratified into quartiles. In the cohort of TJAs cutoffs at 0 to 130 mg/d (0%-25%), 130 to 370 mg/d (25%-75%), and above or equal to 370 mg/d (75%-100%) were used for groups of low, medium, and high opioid utilization, respectively.

Cutoffs for the spine fusion cohort were higher as follows: 0 to 202 mg/d (0%-25%), 202 to 555 mg/d (25%-75%), and above or equal to 550 mg/d (75%-100%), for low, medium, and high opioid utilization, respectively.

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2.5. Outcomes measures

Outcomes of interest were postoperative complications, including myocardial infarction, bradycardia, respiratory, gastrointestinal, and urinary complications, pulmonary embolism (PE), deep venous thrombosis (DVT), cerebrovascular accident, postoperative infection as well as length of stay (LOS) and cost of hospitalization. ICD-9-CM diagnosis codes used to identify major perioperative complications are provided in Appendix A (available online as supplemental digital content at

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2.6. Statistical analysis

Differences in patient and health care–related characteristics were compared between the low, medium and high opioid prescription subgroups. For all variables, absolute numbers of individuals, and percentage in each opioid prescription category were listed with Chi-Squared tests used to formally assess differences between groups.

To determine whether higher opioid prescriptions were associated with outcome measures, multilevel multivariable logistic regression models with random intercepts for binary outcomes of interest were fit. The continuous outcomes LOS and cost were transformed on the log10 scale using multilevel mixed models, as these variables are highly skewed.26,29 Thus, exponentiated coefficients represent percent change from the reference group. In addition, the continuous outcomes LOS and cost were analyzed in a dichotomized approach, by presenting odds ratios and confidence intervals reflecting odds for the occurrence of prolonged LOS and increased cost, defined as LOS and cost above the 75th percentile. Multilevel models consider the multilevel structure of our data and allow adjustment for clustering, relevant in this case at the hospital level. A random intercept for hospitals was included in multilevel models to account for hospital variation,25 and therefore, hospitals with less than 30 patients undergoing the procedures of interest were excluded from this analysis. In all models, we used the lowest opioid prescription category as the reference category and adjusted for confounding factors of age, sex, race, Deyo comorbidity index, obesity, obstructive sleep apnea, history of substance use or abuse, preexistent pain conditions, insurance status, anesthesia technique, and hospital characteristics. The cutoff for statistical significance was set at 0.0045, after adjusting for multiple comparisons using Bonferroni correction.

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3. Results

We identified N = 1,035,578 cases of total hip arthroplasty and total knee arthroplasty, and N = 220,953 cases of elective spine fusions.

Demographics and baseline characteristics of the study cohorts are presented in Tables 1 and 2. Overall, patients undergoing spine surgeries were prescribed significantly higher opioid dosages, compared to the TJA population, evident in differing quartile thresholds. Higher age was associated with lower opioid prescription, while differences were subtle by comorbidity burden.

Table 1

Table 1

Table 2

Table 2

Table 3 presents unadjusted frequencies of postoperative outcomes stratified by quartiles of opioid dosage.

Table 3

Table 3

Generally, complications occurred more frequently in high opioid dose groups, with most pronounced discrepancies by opioid dose for gastrointestinal and thromboembolic complications in descriptive analysis.

Interestingly, unadjusted data showed that myocardial infarctions and cerebrovascular accidents were less frequent in high opioid dose groups as observed in spine patients, with a similar trend in TJA recipients.

Tables 4 and 5 display adjusted odds for postoperative complications, stratified by quartiles of opioid dosage. After adjustment for covariates, higher opioid prescription was associated with significantly higher odds for most, but not all postoperative complications.

Table 4

Table 4

Table 5

Table 5

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.

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4. Discussion

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.

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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

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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

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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

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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.

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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.

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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.

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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.

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4.8. Limitations

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.

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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.

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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 ( 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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[1]. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 2003;97:534–40.
[2]. Austrup ML, Korean G. Analgesic agents for the postoperative period. Opioids Surg Clin North Am 1999;79:253–73.
[3]. Bailey PL, Lu JK, Pace NL, Orr JA, White JL, Hamber EA, Slawson MH, Crouch DJ, Rollins DE. Effects of intrathecal morphine on the ventilatory response to hypoxia. N Engl J Med 2000;343:1228–34.
[4]. Baldini G, Bagry H, Aprikian A, Carli F. Postoperative urinary retention: anesthetic and perioperative considerations. Anesthesiology 2009;110:1139–57.
[5]. Blackshear RH, Crosson KC. Reduction in pulmonary embolism after total joint arthroplasty: three years of experience with extended-release epidural morphine. Pain Pract 2010;10:235–44.
[6]. Borner C, Warnick B, Smida M, Hartig R, Lindquist JA, Schraven B, Hollt V, Kraus J. Mechanisms of opioid-mediated inhibition of human T cell receptor signaling. J Immunol 2009;183:882–9.
[7]. Brennan F, Carr DB, Cousins M. Pain management: a fundamental human right. Anesth Analg 2007;105:205–21.
[8]. Carter JR, Sauder CL, Ray CA. Effect of morphine on sympathetic nerve activity in humans. J Appl Physiol (1985) 2002;93:1764–9.
[9]. Cozowicz C, Poeran J, Zubizarreta N, Mazumdar M, Memtsoudis SG. Trends in the use of regional anesthesia: neuraxial and peripheral nerve blocks. Reg Anesth Pain Med 2016;41:43–9.
[10]. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45:613–19.
[11]. El Solh AA, Bhora M, Pineda L, Dhillon R. Nosocomial pneumonia in elderly patients following cardiac surgery. Respir Med 2006;100:729–36.
[12]. Finucane BT, Ganapathy S, Carli F, Pridham JN, Ong BY, Shukla RC, Kristoffersson AH, Huizar KM, Nevin K, Ahlen KG. Prolonged epidural infusions of ropivacaine (2 mg/mL) after colonic surgery: the impact of adding fentanyl. Anesth Analg 2001;92:1276–85.
[13]. Fryer RM, Hsu AK, Nagase H, Gross GJ. Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive potassium channels. J Pharmacol Exp Ther 2000;294:451–7.
[14]. Gryglewski RJ, Szczeklik A, Bieron K. Morphine antagonises prostaglandin E1- mediated inhibition of human platelet aggregation. Nature 1975;256:56–7.
[15]. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P, Atkins D, Kunz R, Brozek J, Montori V, Jaeschke R, Rind D, Dahm P, Meerpohl J, Vist G, Berliner E, Norris S, Falck-Ytter Y, Murad MH, Schunemann HJ. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol 2011;64:1311–16.
[16]. Islam MR, Yang L, Lee YS, Hruby VJ, Karamyan VT, Abbruscato TJ. Enkephalin-Fentanyl multifunctional opioids as potential neuroprotectants for ischemic stroke treatment. Curr Pharm Des 2016;22:6459–6468.
[17]. Kharasch ED, Brunt LM. Perioperative opioids and public health. Anesthesiology 2016;124:960–5.
[18]. Khodneva Y, Muntner P, Kertesz S, Kissela B, Safford MM. Prescription opioid use and risk of coronary heart disease, stroke, and cardiovascular death among adults from a prospective cohort (regards study). Pain Med 2015;17:444–455.
[19]. Kjaersgaard-Andersen P, Kehlet H. Should deep venous thrombosis prophylaxis be used in fast-track hip and knee replacement? Acta Orthop 2012;83:105–6.
[20]. Lee CW, Muo CH, Liang JA, Sung FC, Kao CH, Yeh JJ. Pulmonary embolism is associated with current morphine treatment in patients with deep vein thrombosis. Clin Respir J 2015;9:233–7.
[21]. Manchikanti L, Helm S II, Fellows B, Janata JW, Pampati V, Grider JS, Boswell MV. Opioid epidemic in the United States. Pain Physician 2012;15(3 suppl):ES9–E38.
[22]. Memtsoudis SG, Poeran J, Cozowicz C, Zubizarreta N, Ozbek U, Mazumdar M. The impact of peripheral nerve blocks on perioperative outcome in hip and knee arthroplasty-a population-based study. PAIN 2016;157:2341–9.
[23]. Memtsoudis SG, Poeran J, Zubizarreta N, Rasul R, Opperer M, Mazumdar M. Anesthetic care for orthopedic patients: is there a potential for differences in care? Anesthesiology 2016;124:608–23.
[24]. Memtsoudis SG, Sun X, Chiu YL, Stundner O, Liu SS, Banerjee S, Mazumdar M, Sharrock NE. Perioperative comparative effectiveness of anesthetic technique in orthopedic patients. Anesthesiology 2013;118:1046–58.
[25]. Moineddin R, Matheson FI, Glazier RH. A simulation study of sample size for multilevel logistic regression models. BMC Med Res Methodol 2007;7:34.
[26]. Moran JL, Solomon PJ. A review of statistical estimators for risk-adjusted length of stay: analysis of the Australian and New Zealand intensive care adult patient data-base, 2008-2009. BMC Med Res Methodol 2012;12:68.
[27]. Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS. Opioids and cardioprotection: the impact of morphine and fentanyl on recovery of ventricular function after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2006;20:493–502.
[28]. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124–36.
[29]. Rascati KL, Smith MJ, Neilands T. Dealing with skewed data: an example using asthma-related costs of medicaid clients. Clin Ther 2001;23:481–98.
[30]. Sanzone AG. Use of nonopioid analgesics and the impact on patient outcomes. J Orthop Trauma 2016;30(suppl 1):S12–S15.
[31]. Savage SR, Joranson DE, Covington EC, Schnoll SH, Heit HA, Gilson AM. Definitions related to the medical use of opioids: evolution towards universal agreement. J Pain Symptom Manage 2003;26:655–67.
[32]. Schultz JE, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res 1996;78:1100–4.
[33]. Schwacha MG, McGwin G Jr, Hutchinson CB, Cross JM, Maclennan PA, Rue LW III. The contribution of opiate analgesics to the development of infectious complications in burn patients. Am J Surg 2006;192:82–6.
[34]. Tanaka K, Kersten JR, Riess ML. Opioid-induced cardioprotection. Curr Pharm Des 2014;20:5696–705.
[35]. Tomai F, Crea F, Gaspardone A, Versaci F, Ghini AS, Ferri C, Desideri G, Chiariello L, Gioffre PA. Effects of naloxone on myocardial ischemic preconditioning in humans. J Am Coll Cardiol 1999;33:1863–9.
[36]. Wang J, Barke RA, Charboneau R, Roy S. Morphine impairs host innate immune response and increases susceptibility to streptococcus pneumoniae lung infection. J Immunol 2005;174:426–34.
[37]. Welters ID, Menzebach A, Goumon Y, Langefeld TW, Teschemacher H, Hempelmann G, Stefano GB. Morphine suppresses complement receptor expression, phagocytosis, and respiratory burst in neutrophils by a nitric oxide and mu(3) opiate receptor-dependent mechanism. J Neuroimmunol 2000;111:139–45.
[38]. Wong TM, Shan J. Modulation of sympathetic actions on the heart by opioid receptor stimulation. J Biomed Sci 2001;8:299–306.
[39]. Xu ZD, Jin M, He WX, Xia SX, Zhao YF, He B, Cao DX, Peng SL, Li J, Cao MH. Remifentanil preconditioning lowers cardiac troponin I levels in patients undergoing off-pump coronary artery bypass graft surgery [in Chinese]. Nan Fang Yi Ke Da Xue Xue Bao 2009;29:1554–6.
[40]. Yang L, Islam MR, Karamyan VT, Abbruscato TJ. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment. Brain Res 2015;1609:1–11.
[41]. Yang L, Wang H, Shah K, Karamyan VT, Abbruscato TJ. Opioid receptor agonists reduce brain edema in stroke. Brain Res 2011;1383:307–16.
[42]. Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: distant dream or near reality? Heart 2000;83:381–7.

Postoperative complications; Opioid prescription; Orthopedic surgery; Opioid dose; Postoperative outcome; Arthroplasty; Postoperative outcome

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© 2017 International Association for the Study of Pain