## Abstract

Editor’s Perspective
• The need for long-duration nonopioid pain relief after total knee arthroplasty has driven multimodal analgesic regimens, some of which include the administration of liposomal bupivacaine

• It is unclear whether the use of liposomal bupivacaine is reliably associated with improvements in clinical or resource outcomes

What This Manuscript Tells Us That Is New
• Retrospective analysis of a national observational data set showed that liposomal bupivacaine use for total knee arthroplasty is increasing

• Liposomal bupivacaine use was not associated with clinically meaningful reductions in inpatient opioid use, opioid-related complications, or resource utilization in patients who received modern pain management including a peripheral nerve block

Background

Although some trials suggest benefits of liposomal bupivacaine, data on real-world use and effectiveness is lacking. This study analyzed the impact of liposomal bupivacaine use (regardless of administration route) on inpatient opioid prescription, resource utilization, and opioid-related complications among patients undergoing total knee arthroplasties with a peripheral nerve block. It was hypothesized that liposomal bupivacaine has limited clinical influence on the studied outcomes.

Methods

The study included data on 88,830 total knee arthroplasties performed with a peripheral nerve block (Premier Healthcare Database 2013 to 2016). Multilevel multivariable regressions measured associations between use of liposomal bupivacaine and (1) inpatient opioid prescription (extracted from billing) and (2) length of stay, cost of hospitalization, as well as opioid-related complications. To reflect the difference between statistical and clinical significance, a relative change of −15% in outcomes was assumed to be clinically important.

Results

Overall, liposomal bupivacaine was used in 21.2% (n = 18,817) of patients that underwent a total knee arthroplasty with a peripheral nerve block. Liposomal bupivacaine use was not associated with a clinically meaningful reduction in inpatient opioid prescription (group median, 253 mg of oral morphine equivalents, adjusted effect −9.3% CI −11.1%, −7.5%; P < 0.0001) and length of stay (group median, 3 days, adjusted effect −8.8% CI −10.1%, −7.5%; P < 0.0001) with no effect on cost of hospitalization. Most importantly, liposomal bupivacaine use was not associated with decreased odds for opioid-related complications.

Conclusions

Liposomal bupivacaine was not associated with a clinically relevant improvement in inpatient opioid prescription, resource utilization, or opioid-related complications in patients who received modern pain management including a peripheral nerve block.

THE management of pain after total knee arthroplasty poses a special challenge to perioperative physicians. Although opioid based regimens remain the cornerstone of postoperative pain control, a multimodal approach involving a combination of opioids, nonopioid analgesics, and regional anesthetic techniques is increasingly being used.1–4  By combining two or more analgesic agents with different mechanisms of action, a multimodal approach should provide adequate pain relief while reducing opioid requirements and opioid-related adverse effects.1,3

In this context, local anesthetics have provided the basis for the performance of peripheral nerve blocks or infiltration techniques, which have been highly effective in reducing pain after joint arthroplasties.5–7  However, their effectiveness has been limited by a relatively short period of action. Catheter approaches have provided the ability to prolong the infusion of local anesthetics but require additional equipment and maintenance and in rare occasions are associated with complications such as infections and inpatient falls.8,9  A recently developed therapy, liposomal bupivacaine, showed promise in addressing these shortfalls. By encapsulating a local anesthetic (bupivacaine) with a lipid-based structure, the local anesthetic is released slowly over time. Thus, liposomal bupivacaine potentially offers the ease of a local infiltration technique along with the longevity associated with a continuous peripheral nerve block. However, its utility in clinical practice remains debated.10,11  Liposomal bupivacaine has been approved by the U.S. Food and Drug Administration for use in local infiltration and interscalene brachial plexus blocks,12  although it is not (yet) recommended for use in other peripheral nerve blocks or for neuraxial or intraarticular use. Therefore, although off-label use may indeed occur, we expect most use of liposomal bupivacaine to be in line with its Food and Drug Administration–approved route.

Although several studies in various general patient populations have shown encouraging results, a number of publications have suggested a limited benefit.13–16  Moreover, previous studies have been limited by several factors, including nonequivalence between comparison groups as well as not following best practices with respect to multimodal analgesia techniques. Moreover, these studies have typically been limited to a single institution, so that population-based data representing everyday practice using liposomal bupivacaine and its effectiveness to reduce opioid use and opioid-related adverse effects are lacking.

Therefore, we used a large national database to study the impact of liposomal bupivacaine (regardless of route of administration) in patients undergoing a total knee arthroplasty, with particular focus on those undergoing the procedure with the utilization of a peripheral nerve block. We analyzed the effect of liposomal bupivacaine use on outcomes. Our primary outcome was inpatient opioid prescription (extracted from billing). Secondary outcomes were opioid-related complications, hospitalization cost, and length of hospital stay. We hypothesized that (1) liposomal bupivacaine was used in the minority of cases, (2) utilization was increasing over time, and (3) liposomal bupivacaine has limited clinical influence on the studied outcomes in patients who received multimodal analgesia including peripheral nerve blocks.

## Materials and Methods

### Data Source, Study Design, and Study Sample

This retrospective cohort study was considered exempt by the Institutional Review Boards of the Mount Sinai Hospital (New York, New York; approval No. 14-00647) and the Hospital for Special Surgery (New York, New York; approval No. 2012-050) due to the deidentified nature of the data. The data source was the nationwide all-payer Premier Healthcare database (Premier Inc., USA), which contains detailed billing information on 20 to 25% of U.S. hospitalizations.17,18  The study sample was created using the International Classification of Diseases, Ninth Revision (ICD-9) procedure code for primary knee replacement (81.54). The cohort contained patients undergoing surgery from January 1, 2013, to December 31, 2016. From this sample, we selected patients that received a peripheral nerve block (n = 100,795). Patients were excluded in case of nonelective procedures (n = 1,852), unknown discharge status (n = 9), an outpatient procedure (n = 477), treatment at a hospital performing less than 30 total knee arthroplasties (to ensure sufficient sample size per hospital; n = 715),19  absent billing for inpatient opioid prescription (n = 4,268), and inpatient opioid prescription above the 95th percentile (n = 4,644). The latter two exclusion criteria were applied to account for extremes and potentially unreliable billing for opioids. The Premier data have been used in numerous population-based studies examining health outcomes.20–22  After applying the exclusion criteria, there were no missing data for any variable of interest. We specifically aimed to perform our main analyses in a cohort of patients receiving peripheral nerve blocks to analyze the impact of liposomal bupivacaine in a setting in which state-of-the-art pain management was practiced; this decision was made a priori.

### Study Variables

An analysis plan was created a priori that identified all relevant study variables including the main effect of interest and outcomes. The main effect of interest was the use of liposomal bupivacaine; a binary variable was created based on billing for liposomal bupivacaine. Unfortunately, using the Premier data set, we were not able to differentiate between the various routes of liposomal bupivacaine administration. However, we expect most liposomal bupivacaine to be used in line with its Food and Drug Administration–approved administration modality (local infiltration). Use of a peripheral nerve block was determined by a combination of billed charges and Current Procedural Terminology codes as previously defined.23

The primary outcome was inpatient opioid prescription. This was extracted from billing for opioids and converted to oral morphine equivalents using the Lexicomp “opioid agonist conversion” and the GlobalRPH “opioid analgesic converter.”24,25  We used this as a proxy for opioid administration, recognizing that this may lead to an overestimation because not everything billed for may be actually administered. This bias, however, is minimized because we expect this likely overestimation to be independent of liposomal bupivacaine use and thus affect both groups equally.

Secondary outcomes were length and cost of hospitalization and opioid-related complications including respiratory, gastrointestinal, central nervous system, genitourinary, and “other” (composite of ICD-9 codes for postoperative bradycardia, rash or itching, drugs causing adverse effects with therapeutic use, and fall from bed) complications.26  Inpatient opioid prescription (in mg oral morphine equivalents) was categorized into prescription totals for the entire hospitalization and totals for the day of surgery (day 0), the day after (day 1), and the subsequent days (day 1+). Cost of hospitalization was adjusted for inflation and reported in 2016 U.S. dollars. Length of stay was reported in days.

Patient demographics included age, sex, and race (white, black, other). Healthcare-related variables included insurance type (commercial, Medicaid, Medicare, uninsured, other), hospital location (urban, rural), hospital size (less than 300, 300 to 499, at least 500 beds), hospital teaching status, and the annual number of total knee arthroplasties performed per hospital. Procedure-related variables included the year of the procedure, the use of neuraxial anesthesia, the use of general anesthesia, patient-controlled analgesia, and use of nonopioid analgesics (IV acetaminophen, gabapentin/pregabalin [gabapentinoids], nonsteroidal antiinflammatory drugs [NSAIDs], cyclooxygenase-2 inhibitors, and ketamine). Overall comorbidity burden was assessed using the Quan et al. adaptation of the Charlson–Deyo Comorbidity Index.27  In addition, we included separate variables indicating substance use/abuse (including smoking), chronic pain conditions, and psychiatric comorbidity variables because they may influence particularly inpatient opioid prescription. The definitions of these variables can be found in Supplemental Digital Content 1 (http://links.lww.com/ALN/B719).

As is typical when using population-based data (i.e., data not specifically collected for any specific study), variables may be under- or overreported. This holds particularly true for inpatient opioid utilization because the amount billed for may not necessarily reflect the amount administered; thus, a potential overestimation may occur. However, numbers from the current study fall in line with those reported in other studies.28–30  For opioid-related complications, we expect an underreporting because they are defined using ICD-9 codes for which a limited number of fields exist per case. We expect cost and length of stay to be accurate because that is the main focus of the Premier Healthcare data set (i.e., economic benchmarking for hospitals).18

### Statistical Analysis

Univariable associations between liposomal bupivacaine use and study variables were analyzed using the chi-square test and t test for categorical and continuous variables, respectively. Multilevel, multivariable regression models were fit to measure associations between liposomal bupivacaine use and outcomes. Multilevel models account for correlation of patients within hospitals (i.e., patients are “nested” within each hospital) and fit one regression line for each hospital, based on all patients within a given hospital.31  This adjustment is necessary because patients within hospitals are correlated as they may experience similar care (e.g., equal chance of liposomal bupivacaine for patients within the same hospital).

Covariates used in the multilevel models were chosen based on clinical importance and/or univariable significance at the P < 0.15 level.32  The final covariates in the model are age, hospital-specific annual volume of total knee arthroplasties, hospital size, Charlson–Deyo Index, sex, race, year, insurance type, hospital teaching status, hospital location, general anesthesia use, neuraxial anesthesia use, liposomal bupivacaine, NSAIDs, cyclooxygenase-2 inhibitors, ketamine, gabapentinoids, patient-controlled analgesia, IV acetaminophen, and the comorbidity variables indicating substance use/abuse, chronic pain conditions, and psychiatric conditions. Full model coefficients can be found in Supplemental Digital Content 2 (http://links.lww.com/ALN/B720). Effect estimates are reported as adjusted odds ratios with Bonferroni-adjusted P values and 95% CI, which will reduce the risk of type I errors, whereas the likelihood of type II errors may be increased.33  Model discrimination was evaluated using the c-statistic (area under the receiver operating curve). A c-statistic value of 0.7 or higher shows good discrimination.34

All analyses were done using the PROC GLIMMIX procedure in SAS v9.4 statistical software (SAS Institute, USA). For the continuous outcomes of inpatient opioid prescription, cost of hospitalization, and length of stay, the γ distribution with a log-link function was used as these variables are skewed.35,36  Effect estimates for these outcomes are reported as percentage change and confidence intervals.

The PROC GLIMMIX procedure was additionally used to determine the intraclass correlation coefficient, which estimates the percentage of variation in liposomal bupivacaine use that is accounted for by hospitals included in our study.37  A high percentage would indicate that liposomal bupivacaine use is mainly determined by hospital-level factors.

### Sensitivity Analysis

We performed a sensitivity analysis to address the possible issue of confounding by indication with patients receiving liposomal bupivacaine because of greater pain and thus more likely to have increased inpatient opioid prescription. To address this potential bias, the sensitivity analysis was performed in a cohort restricted to hospitals with at least 50% liposomal bupivacaine use, which may indicate that these hospitals have a perioperative pain protocol that includes liposomal bupivacaine, hence negating the idea of confounding by indication.

### Statistical and Clinical Significance

As recommended, we judged our inpatient opioid prescription and resource utilization results in respect to their clinically meaningful significance by a priori designating an at least −15% reduction of the reported outcome as clinically meaningful. Authors studying opioid-related complications have suggested that this reduction should be at least 25%.38  Thus, our threshold should be considered less stringent. Statistical significance is reported at the traditional P < 0.05 value.

### A Priori versus Post Hoc Analyses

Through the course of the peer-review process, we made adjustments to our initial a priori specified analyses. Specifically, we performed the same analyses as mentioned above in two separate cohorts: (1) patients undergoing total knee arthroplasty with a peripheral nerve block and use of general anesthesia and (2) patients undergoing total knee arthroplasty with a peripheral nerve block and use of neuraxial anesthesia.

The reasoning behind these additional analyses is that we expect a more pronounced effect of liposomal bupivacaine among patients with a higher (general anesthesia patients) compared to a lower (neuraxial anesthesia patients) baseline opioid utilization. Use of general and neuraxial anesthesia is defined through the Premier billing file as previously described.23  An additional analysis was performed to assess whether using the individual comorbidities making up the index in our multivariable models would produce different results compared to the use of the Charlson–Deyo index itself.

## Results

We identified 88,830 hospitalizations from 2013 to 2016 during which a total knee arthroplasty was performed using a peripheral nerve block. Liposomal bupivacaine was used in 21.2% (n = 18,817) of patients with substantial interhospital variation in liposomal bupivacaine use ranging from 0 to 99.5% (interquartile range: 0 to 40.1%) (fig. 1). In addition, use of liposomal bupivacaine increased over time from 7.1% in 2013 to 25.5% in 2016, respectively.

Fig. 1.

Interhospital variation (with interquartile range [IQR]) in liposomal bupivacaine use.

Fig. 1.

Interhospital variation (with interquartile range [IQR]) in liposomal bupivacaine use.

Table 1 shows patient demographics, healthcare-related, and procedure-related variables and comorbidities by use of liposomal bupivacaine. Differences in patient demographics, comorbidities, and insurance type were small between those receiving and not receiving liposomal bupivacaine. Use of liposomal bupivacaine was higher in urban, small- and medium-sized, and nonteaching hospitals. Institutions using liposomal bupivacaine performed a higher number of total knee arthroplasties on an annual basis. Of note, patients who received liposomal bupivacaine also received other nonopioid analgesic medication significantly more often than the control group, except for NSAIDs and ketamine.

Table 1.

Patient Demographics, Healthcare-related, Procedure-related, and Comorbidity-related Variables (Chi-Square and t Tests for Categorical and Continuous Variables, Respectively) by Liposomal Bupivacaine Use in the Peripheral Nerve Block Cohort

Table 2 details the prevalence of complications and provides information on inpatient opioid prescription, cost and length of hospitalization, and outcomes from multivariable models. In general, absolute rates of complications in patients who received liposomal bupivacaine were marginally lower compared to those who did not receive liposomal bupivacaine. Univariable results showed that patients in the liposomal bupivacaine group had lower inpatient opioid prescription (190 vs. 272 median mg oral morphine equivalents), length of stay (2 vs. 3 median days), and cost of hospitalization ($15,013 vs.$15,810 median dollars). However, when controlling for relevant covariates, the use of liposomal bupivacaine was associated with no clinically meaningful reduction in overall inpatient opioid prescription (adjusted effect, −9.3%; CI −11.1%, −7.5%; P < 0.0001) and length of stay (−8.8%; CI −10.1%, −7.5%; P < 0.0001) and a nonsignificant increase in cost of hospitalization (+2.2%; CI −0.1%, +4.6%; P = 0.0900).

Table 2.

Univariable (Chi-Square and t Test for Categorical and Continuous Variables, Respectively) and Multivariable Results by Liposomal Bupivacaine Use in the Peripheral Nerve Block Cohort

Furthermore, liposomal bupivacaine use was not associated with significantly lower odds for opioid-related complications in patients undergoing a total knee arthroplasty with a peripheral nerve block. The c-statistics for the associated models varied between 0.75 and 0.79 indicating sufficient model discrimination. The intraclass correlation coefficient demonstrated that 79% of the variability in liposomal bupivacaine use can be accounted for by hospital-level factors.

Sensitivity analyses restricting the cohort to hospitals with more than 50% liposomal bupivacaine use showed similar effect estimates for inpatient opioid prescription and length and cost of hospitalization (tables 3 and 4). Supplemental Digital Content 3 to 6 (http://links.lww.com/ALN/B721, http://links.lww.com/ALN/B722, http://links.lww.com/ALN/B723, http://links.lww.com/ALN/B724) depict the same analyses in two subgroups of patients undergoing total knee arthroplasty with a peripheral nerve block and (1) general anesthesia or (2) neuraxial anesthesia. Multivariable results in these cohorts also showed a nonclinically significant reduction in inpatient opioid prescription associated with the use of liposomal bupivacaine when compared to no liposomal bupivacaine use. However, the effect was more pronounced in the general anesthesia subgroup (−12.3%; CI −14.8%, −9.7%; P < 0.0001), whereas in the neuraxial anesthesia subgroup the reduction was not statistically significant (−6.1%; CI −14.6%, 3.2%; P > 0.999).

Table 3.

Patient Demographics, Healthcare-related, Procedure-related, and Comorbidity-related Variables (Chi-Square and t Tests for Categorical and Continuous Variables, Respectively) by Liposomal Bupivacaine Use for the Sensitivity Analysis in Hospitals with More than 50% Liposomal Bupivacaine Use

Table 4.

Univariable (t Test for Comparisons) and Multivariable Results by Liposomal Bupivacaine Use for the Sensitivity Analysis in Hospitals with More than 50% Liposomal Bupivacaine Use

In addition, we performed an analysis to assess whether using the individual Charlson–Deyo comorbidities in our multivariable models would produce different results compared to the use of the Charlson–Deyo index. Liposomal bupivacaine was associated with −9.3% (CI −10.4%, −8.2%) reduction in total inpatient opioid prescription when using a model with individual comorbidities; this was −9.3% (CI −11.1%, −7.5%) when using a model with the Charlson–Deyo index. Because the results are essentially unaltered, we opted to continue using the Charlson–Deyo index in our multivariable models.

## Discussion

In this observational study of 88,830 total knee arthroplasties in patients who also received a peripheral nerve block, we were unable to determine an association between liposomal bupivacaine use and clinically meaningful reductions in inpatient opioid prescription. Furthermore, no relevant impact of liposomal bupivacaine use on complications or resource utilization was observed. Our sensitivity analyses supported results from our main analysis, demonstrating the robustness of our results. Although only a minority of patients (21.2%) received liposomal bupivacaine, an initial increase in the utilization of this product was seen over time. Utilization reached a plateau in the latter 2 yr of the study. In addition, we demonstrated substantial interhospital variation in the use of liposomal bupivacaine, which was also reflected in the intraclass correlation coefficient.

The reasons for the variability in liposomal bupivacaine use have to remain speculative but are likely to include physician and patient preference. We have previously shown that pain management modalities vary widely among hospitals.39  Factors influencing the choice to use a certain medication may be institution- and provider-related. They may include differences in experience and training, the use of protocols and cost considerations.40  Although the rapid increase in its utilization in the first 3 yr on the market can be attributed to the fact that liposomal bupivacaine is a new drug, approved by the Food and Drug Administration in 2011, this trend may also reflect the growing awareness for opioid-related adverse effects and the desire to reduce them.41,42  A more recent reduction, however, is noteworthy, and although no firm conclusions can be drawn from our data, this finding may at least in part be explained by the lack of data supporting its efficacy in this patient population in the context of its relatively high cost.

We did not observe a clinically meaningful reduction in inpatient opioid prescription and resource utilization outcomes. Moreover, liposomal bupivacaine use was not associated with any difference in opioid-related complications. This suggests that in the context of state-of-the-art pain management including peripheral nerve blocks, liposomal bupivacaine may have a limited role. This is in line with a recent publication by Amundson et al.,10  suggesting that liposomal bupivacaine is inferior to the use of femoral catheters plus sciatic blocks in total knee arthroplasties. The authors of this study also found that liposomal bupivacaine was not superior to a ropivacaine mixture.

Bagsby et al.14  also demonstrated that a periarticular liposomal bupivacaine injection in primary total knee arthroplasty patients had no benefit over ropivacaine regarding pain and opioid usage. The authors concluded that when a multimodal pain protocol is being used, liposomal bupivacaine does not beneficially influence pain control. Similar results have been reported by Schroer et al.13  In their prospective, blinded, randomized study of 111 patients undergoing a total knee arthroplasty and receiving a multimodal pain therapy, they found no benefit of liposomal bupivacaine over bupivacaine.

On the other hand, there is a variety of studies that suggest a positive effect of liposomal bupivacaine in total knee arthroplasty. However, some of those studies do not include comparable control groups. In a recent publication, Mont et al.43  concluded that local infiltration of liposomal bupivacaine improves pain scores and opioid use after total knee arthroplasty. However, because the control group received significantly lower amounts of local anesthetics (100 mg of bupivacaine in the control group vs. 100 mg of bupivacaine plus 266 mg of liposomal bupivacaine in the study group), it does not seem surprising that the study group had better outcomes. Next to questionable control groups, currently published studies do not address the fact that potential efficacy of liposomal bupivacaine in highly selective trials may not translate to effectiveness in real-world settings. Indeed, while focusing on its safety profile, liposomal bupivacaine gained Food and Drug Administration acceptance based on trials performed in patients undergoing bunionectomies and hemorrhoidectomies,44,45  a far cry from its widespread utilization in much larger surgeries characterized by more pain and opioid utilization.

Interestingly, we found that in those patients within the peripheral nerve block cohort that received general anesthesia, liposomal bupivacaine was associated with a more pronounced reduction in inpatient opioid prescription compared to those that received neuraxial anesthesia. Although this may be due to the higher baseline opioid utilization (as demonstrated by the higher inpatient opioid prescription) in this cohort, this further questions the value of liposomal bupivacaine in light of real-world practices where state-of-the-art anesthetic and pain management is used, including peripheral nerve blocks and neuraxial anesthesia/analgesia.

In conclusion, we failed to show a clinically meaningful reduction in either inpatient opioid prescription, opioid-related complications, or resource utilization outcomes among patients receiving liposomal bupivacaine as part of their total knee arthroplasty. Given the number of recent publications that suggest a lack of benefit of the addition of liposomal bupivacaine to a multimodal regimen including a regional analgesic technique, its routine use should be carefully examined, especially given its relatively high cost. Future studies will need to evaluate the effectiveness of liposomal bupivacaine separately for the different routes of administration.

## Research Support

Supported by National Institute on Drug Abuse, Rockville, Maryland, grant No. K08DA032314 (to Dr. Sun), consulting fees unrelated to this work from Egalet Inc., Wayne, Pennsylvania (to Dr. Sun) and by the Tisch Cancer Institute at Mount Sinai, New York, New York (to Dr. Mazumdar and Dr. Poeran). For all the other authors, support was provided solely from institutional and/or departmental sources.

## Competing Interests

Dr. Memtsoudis is a director on the boards of the American Society of Regional Anesthesia and Pain Medicine, Pittsburgh, Pennsylvania, and the Society of Anesthesia and Sleep Medicine, Milwaukee, Wisconsin. He is a one-time consultant for Sandoz Inc., Princeton, New Jersey, and the holder of U.S. Patent US-2017-0361063, Multicatheter Infusion System. He is the owner of SGM Consulting, LLC, Rumson, New Jersey, and co-owner of FC Monmouth, LLC, Fairhaven, New Jersey. None of the above relations influenced the conduct of the present study. The other authors declare no competing interests.

## References

1.
Fu
PL
,
Xiao
J
,
Zhu
YL
,
Wu
HS
,
Li
XH
,
Wu
YL
,
Qian
QR
:
Efficacy of a multimodal analgesia protocol in total knee arthroplasty: A randomized, controlled trial.
J Int Med Res
2010
;
38
:
1404
12
2.
Grosu
I
,
Lavand’homme
P
,
Thienpont
E
:
Pain after knee arthroplasty: An unresolved issue.
Knee Surg Sports Traumatol Arthrosc
2014
;
22
:
1744
58
3.
Hebl
JR
,
Dilger
JA
,
Byer
DE
,
Kopp
SL
,
Stevens
SR
,
Pagnano
MW
,
Hanssen
,
Horlocker
TT
:
A pre-emptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery.
Reg Anesth Pain Med
2008
;
33
:
510
7
4.
Kelley
TC
,
MJ
,
Mulliken
BD
,
Dalury
DF
:
Efficacy of multimodal perioperative analgesia protocol with periarticular medication injection in total knee arthroplasty: A randomized, double-blinded study.
J Arthroplasty
2013
;
28
:
1274
7
5.
Paul
JE
,
Arya
A
,
Hurlburt
L
,
Cheng
J
,
Thabane
L
,
Tidy
A
,
Murthy
Y
:
Femoral nerve block improves analgesia outcomes after total knee arthroplasty: A meta-analysis of randomized controlled trials.
Anesthesiology
2010
;
113
:
1144
62
6.
Wiesmann
T
,
Steinfeldt
T
,
Wagner
G
,
Wulf
H
,
Schmitt
J
,
Zoremba
M
:
Supplemental single shot femoral nerve block for total hip arthroplasty: Impact on early postoperative care, pain management and lung function.
Minerva Anestesiol
2014
;
80
:
48
57
7.
Marques
EM
,
Jones
HE
,
Elvers
KT
,
Pyke
M
,
Blom
AW
,
Beswick
:
Local anaesthetic infiltration for peri-operative pain control in total hip and knee replacement: Systematic review and meta-analyses of short- and long-term effectiveness.
BMC Musculoskelet Disord
2014
;
15
:
220
8.
Ilfeld
BM
:
Continuous peripheral nerve blocks: A review of the published evidence.
Anesth Analg
2011
;
113
:
904
25
9.
Ilfeld
BM
,
Duke
KB
,
Donohue
MC
:
The association between lower extremity continuous peripheral nerve blocks and patient falls after knee and hip arthroplasty.
Anesth Analg
2010
;
111
:
1552
4
10.
Amundson
AW
,
Johnson
RL
,
Abdel
MP
,
Mantilla
CB
,
Panchamia
JK
,
Taunton
MJ
,
Kralovec
ME
,
Hebl
JR
,
Schroeder
DR
,
Pagnano
MW
,
Kopp
SL
:
A three-arm randomized clinical trial comparing continuous femoral plus single-injection sciatic peripheral nerve blocks versus periarticular injection with ropivacaine or liposomal bupivacaine for patients undergoing total knee arthroplasty.
Anesthesiology
2017
;
126
:
1139
50
11.
Vandepitte
C
,
Kuroda
M
,
Witvrouw
R
,
Anne
L
,
Bellemans
J
,
Corten
K
,
Vanelderen
P
,
Mesotten
D
,
Leunen
I
,
Heylen
M
,
Van Boxstael
S
,
Golebiewski
M
,
Van de Velde
M
,
Knezevic
NN
,
A
:
Addition of liposome bupivacaine to bupivacaine HCl versus bupivacaine HCl alone for interscalene brachial plexus block in patients having major shoulder surgery.
Reg Anesth Pain Med
2017
;
42
:
334
41
12.
FDA information on approval of liposomal bupivacaine
.
13.
Schroer
WC
,
Diesfeld
PG
,
LeMarr
AR
,
Morton
DJ
,
Reedy
ME
:
Does extended-release liposomal bupivacaine better control pain than bupivacaine after total knee arthroplasty (TKA)?: A prospective, randomized clinical trial.
J Arthroplasty
2015
;
30
:
64
7
14.
Bagsby
DT
,
Ireland
PH
,
Meneghini
RM
:
Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty.
J Arthroplasty
2014
;
29
:
1687
90
15.
Sakamoto
B
,
Keiser
S
,
Meldrum
R
,
Harker
G
,
Freese
A
:
Efficacy of liposomal bupivacaine infiltration on the management of total knee arthroplasty.
JAMA Surg
2017
;
152
:
90
5
16.
Webb
BT
,
Spears
JR
,
Smith
LS
,
Malkani
AL
:
Periarticular injection of liposomal bupivacaine in total knee arthroplasty.
Arthroplast Today
2015
;
1
:
117
20
17.
R
,
Ryan
PB
:
Transforming the premier perspective hospital database into the Observational Medical Outcomes Partnership (OMOP) common data model.
EGEMS (Wash DC)
2014
;
2
:
1110
19.
Moineddin
R
,
Matheson
FI
,
Glazier
RH
:
A simulation study of sample size for multilevel logistic regression models.
BMC Med Res Methodol
2007
;
7
:
34
20.
Thacker
JK
,
Mountford
WK
,
Ernst
FR
,
Krukas
MR
,
Mythen
MM
:
Perioperative fluid utilization variability and association with outcomes: Considerations for enhanced recovery efforts in sample US surgical populations.
Ann Surg
2016
;
263
:
502
10
21.
Magee
G
,
Zaloga
GP
,
Turpin
RS
,
Sanon
M
:
A retrospective, observational study of patient outcomes for critically ill patients receiving parenteral nutrition.
Value Health
2014
;
17
:
328
33
22.
Cozowicz
C
,
Olson
A
,
Poeran
J
,
Mörwald
EE
,
Zubizarreta
N
,
Girardi
FP
,
Hughes
AP
,
Mazumdar
M
,
Memtsoudis
SG
:
Opioid prescription levels and postoperative outcomes in orthopedic surgery.
Pain
2017
;
158
:
2422
30
23.
Memtsoudis
SG
,
Danninger
T
,
Rasul
R
,
Poeran
J
,
Gerner
P
,
Stundner
O
,
Mariano
ER
,
Mazumdar
M
:
Inpatient falls after total knee arthroplasty: The role of anesthesia type and peripheral nerve blocks.
Anesthesiology
2014
;
120
:
551
63
24.
Wolters Kluwer Clinical Drug Information, Inc. Opioid Agonist Conversion
.
Available at: http://online.lexi.com/lco/action/calc/calculator/70050. Accessed September 19, 2016
25.
McAuley
D
:
GlobalRPH Opioid Analgesic Converter.
Available at: http://globalrph.com/narcoticonv.htm. Accessed September 19, 2016
26.
Kessler
ER
,
Shah
M
,
Gruschkus
SK
,
Raju
A
:
Cost and quality implications of opioid-based postsurgical pain control using administrative claims data from a large health system: Opioid-related adverse events and their impact on clinical and economic outcomes.
Pharmacotherapy
2013
;
33
:
383
91
27.
Quan
H
,
Sundararajan
V
,
Halfon
P
,
Fong
A
,
Burnand
B
,
Luthi
JC
,
Saunders
LD
,
Beck
CA
,
Feasby
TE
,
Ghali
WA
:
Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
Med Care
2005
;
43
:
1130
9
28.
Lee
S
,
Rooban
N
,
H
,
Sawka
AN
,
Tang
R
:
A randomized non-inferiority trial of adductor canal block for analgesia after total knee arthroplasty: Single injection versus catheter technique.
J Arthroplasty
2018
;
33
:
1045
51
29.
Raiff
D
,
Vaughan
C
,
McGee
A
:
Impact of intraoperative acetaminophen administration on postoperative opioid consumption in patients undergoing hip or knee replacement.
Hosp Pharm
2014
;
49
:
1022
32
30.
Sing
DC
,
Barry
JJ
,
Cheah
JW
,
Vail
TP
,
Hansen
EN
:
Long-acting opioid use independently predicts perioperative complication in total joint arthroplasty.
J Arthroplasty
2016
;
31
:
170
174.e1
31.
Witte
JS
,
Greenland
S
,
Kim
LL
,
Arab
L
:
Multilevel modeling in epidemiology with GLIMMIX.
Epidemiology
2000
;
11
:
684
8
32.
Harrell
FE
:
Regression modeling strategies
.
New York
,
Springer
,
2001
, pp
568
33.
Perneger
TV
:
BMJ
1998
;
316
:
1236
8
34.
Hosmer
DW
,
Lemesbow
S
:
Goodness of fit tests for the multiple logistic regression model.
Commun Stat Theory Methods
1980
;
9
:
1043
69
35.
Moran
JL
,
Solomon
PJ
;
ANZICS Centre for Outcome and Resource Evaluation (CORE) of the Australian and New Zealand Intensive Care Society (ANZICS)
:
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
36.
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
37.
Ene
M
,
Leighton
EA
,
Blue
GL
,
Bell
BA
:
Multilevel models for categorical data using SAS® PROC GLIMMIX: The basics.
SouthEast SAS Users Group Paper 134–2014. Available at: http://analytics.ncsu.edu/sesug/2014/SD-13.pdf. Accessed December 19, 2017
38.
Cherny
N
,
Ripamonti
C
,
Pereira
J
,
Davis
C
,
Fallon
M
,
McQuay
H
,
S
,
Pasternak
G
,
Ventafridda
V
;
Expert Working Group of the European Association of Palliative Care Network
:
Strategies to manage the adverse effects of oral morphine: An evidence-based report.
J Clin Oncol
2001
;
19
:
2542
54
39.
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
40.
Pomerleau
AC
,
Schrager
JD
,
Morgan
BW
:
Pilot study of the importance of factors affecting emergency department opioid analgesic prescribing decisions.
J Med Toxicol
2016
;
12
:
282
8
41.
Rice
DC
,
Cata
JP
,
Mena
GE
,
Rodriguez-Restrepo
A
,
Correa
AM
,
Mehran
RJ
:
Posterior intercostal nerve block with liposomal bupivacaine: An alternative to thoracic epidural analgesia.
Ann Thorac Surg
2015
;
99
:
1953
60
42.
Stone
AB
,
Wick
EC
,
Wu
CL
,
Grant
MC
:
The US opioid crisis: A role for enhanced recovery after surgery.
Anesth Analg
2017
;
125
:
1803
5
43.
Mont
MA
,
Beaver
WB
,
Dysart
SH
,
Barrington
JW
,
Del Gaizo
DJ
:
Local infiltration analgesia with liposomal bupivacaine improves pain scores and reduces opioid use after total knee arthroplasty: Results of a randomized controlled trial.
J Arthroplasty
2017
;
33
:
90
6
44.
Golf
M
,
Daniels
SE
,
Onel
E
:
A phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy.
2011
;
28
:
776
88
45.
Gorfine
SR
,
Onel
E
,
Patou
G
,
Krivokapic
ZV
:
Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: A multicenter, randomized, double-blind, placebo-controlled trial.
Dis Colon Rectum
2011
;
54
:
1552
9
46.
Kim
KY
,
Anoushiravani
AA
,
Chen
KK
,
Roof
M
,
Long
WJ
,
Schwarzkopf
R
:
Preoperative chronic opioid users in total knee arthroplasty: Which patients persistently abuse opiates following surgery?
J Arthroplasty
2018
;
33
:
107
12
47.
Smith
SR
,
Bido
J
,
Collins
JE
,
Yang
H
,
Katz
JN
,
Losina
E
:
Impact of preoperative opioid use on total knee arthroplasty outcomes.
J Bone Joint Surg Am
2017
;
99
:
803
8