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Preemptive Analgesia With Oxycodone Is Associated With More Pain Following Total Joint Arthroplasty
The Journal of Arthroplasty xxx (2019) 1e6
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Preemptive Analgesia With Oxycodone Is Associated With More Pain Following Total Joint Arthroplasty H. John Cooper, MD a, *, Akshay Lakra, MD a, Robert B. Maniker, MD b, Thomas R. Hickernell, MD a, Roshan P. Shah, MD a, Jeffrey A. Geller, MD a a b
Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY Department of Anesthesiology, Columbia University Medical Center, New York, NY
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 June 2018 Received in revised form 12 July 2019 Accepted 17 July 2019 Available online xxx
Background: Preemptive multimodal analgesia (PMA) is a commonly used technique to control pain following total joint arthroplasty. PMA protocols use multiple analgesics immediately preoperatively to prevent central sensitization and amplification of pain during surgery. While benefits of some individual components of a PMA protocol have been established, there are little data to support inclusion or exclusion of opioids in this context. Methods: This is a retrospective cohort study of 550 patients undergoing elective, primary total joint arthroplasty at a single institution using a standardized preoperative perioperative protocol. Two hundred seventy-five patients received oxycodone in addition to a standard multimodal preoperative analgesia regimen just before surgery and were compared to a matched cohort of 275 patients who received the standard regimen alone. Outcome measures included inpatient visual analog scale pain scores, inpatient opioid consumption, length of stay, and ambulation distance with physical therapy. Results: Patients who received opioids in preoperative holding reported significantly greater visual analog scale pain scores on postoperative day 1 (3.7 vs 3.1; P ¼ .01), when compared to those who did not. These patients also walked shorter distances on postoperative day 0 (59.5’ vs 125.7’; P < .001) and consumed greater morphine equivalents per hospital day over the course of their hospital stay (52.2 vs 37.2 mg; P < .001). These differences remained significant when stratified by procedure, total knee arthroplasty or total hip arthroplasty. Differences in pain and function between groups were more pronounced in patients undergoing total hip arthroplasty than those undergoing total knee arthroplasty. Conclusion: Total joint patients who were given preemptive opioids immediately before surgery experienced more pain, consumed more postoperative opioids, and exhibited impaired early function as compared to those who were not given preemptive opioids. Orthopedic surgeons should reconsider routine use of preemptive opioids in this context. © 2019 Elsevier Inc. All rights reserved.
Keywords: opioid-induced hyperalgesia oxycodone pain preemptive analgesia total hip arthroplasty total knee arthroplasty
Ethical Review Committee Statement: This study was approved by our institutional review board (IRB-AAAR5714) and conducted in accordance with the ethical standards in the 1964 Declaration of Helsinki. This work was performed in the Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY. One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.arth.2019.07.021. * Reprint requests: H. John Cooper, MD, Department of Orthopedic Surgery, Columbia University Medical Center, 622 W 168th St, PH-11, New York, NY 10032. https://doi.org/10.1016/j.arth.2019.07.021 0883-5403/© 2019 Elsevier Inc. All rights reserved.
Pain following total joint arthroplasty is a significant concern for our patients [1]. Poorly controlled postoperative pain causes unnecessary discomfort and dissatisfaction, limits recovery and rehabilitation, increases cost and length of stay (LOS), and leads to worse outcomes [2e6]. Multimodal analgesia is the combination of relatively low doses of multiple different medication classes in order to maximize analgesia while minimizing side effects. Preemptive multimodal analgesia (PMA) is a commonly used method of addressing postoperative pain, wherein multimodal analgesia is initiated before the painful stimulus with the goals of preventing central sensitization and amplification of pain during surgery [7]. Preoperative PMA was introduced and widely adopted in centers performing total joint arthroplasty over the past 15 years [8e18],
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and in conjunction with evolving regional anesthesia techniques and local periarticular injections, has been effective in decreasing the overall use of opioids, decreasing postoperative pain, decreasing LOS, and facilitating more rapid mobilization [8e10,13,16,19,20]. Specific preoperative PMA regimens vary throughout the literature, but typically consist of a selective COX-2 inhibitor [8e10,12e16,18,19,21e23] and an extended-release opioid [8e10,12e19], with some centers adding other modalities such as acetaminophen [17,21e23], gabapentinoids [12,17,19,21e24], or peripheral nerve blocks [9,12,19] to this “preoperative cocktail.” The conceptual framework of preoperative PMA makes sense intuitively, aiding its widespread adoption across many orthopedic centers without rigorous analysis of the individual components of the preoperative regimen. While several individual medications in the multimodal analgesic approach have been studied in isolation, others have not, leaving open the possibility that some components of the preoperative PMA regimen may not be helpful and may actually be counterproductive in controlling postoperative pain. Of all pharmacologic options for preemptive analgesia, opioids are of particular concern for many reasons. Opioids pose risks of acute and chronic tolerance, dependence, diversion, and opioidinduced hyperalgesia (OIH). Briefly, OIH is a state of nociceptive sensitization caused by (even brief) exposure to opioids, characterized by a paradoxical response wherein patients become more
Table 1 Patient Demographics and Clinical Outcomes. Variables Age Gender Female (%) Male (%) BMI ASA Preoperative diagnosis OA (%) Other (%) Length of stay Anesthesia type Spinal (%) General (%) Adductor canal block (for TKA only) Periarticular injection Operative time (min) Intraoperative MMEs Discharge disposition Home (%) Outside (%) VAS pain scores (1-10) POD0 POD1 POD2 Number of feet walked POD0 POD1 POD2 Morphine equivalents (mg) POD0 POD1 POD2 Morphine equivalents/d
Oxy (N ¼ 275)
Without Oxy (N ¼ 275)
63.1 ± 11.5
64.0 ± 12.6
.40
165 (60%) 110 (40%) 29.6 ± 8.2 2.2 ± 0.51
166 (60.4%) 109 (39.6%) 29.0 ± 5.6 2.2 ± 0.52
.40a .36 .16
242 (88%) 33 (12%) 2.3 ± 0.99
243 (88.4%) 32 (11.6%) 2.3 ± 1.4
.85a .94
244 (88.7%) 31 (11.3%) 75 (65%)
245 (89.1%) 30 (10.9%) 82 (71%)
.85 .17a
268 (97.5%) 112.7 ± 24.4 9.4 ± 7.9
263 (95.6%) 112.4 ± 25.4 8.5 ± 9.0
.14a .90 .21
232 (84.4%) 43 (15.6%)
233 (84.7%) 42 (15.3%)
.87a,b
3.2 ± 2.9 3.7 ± 2.6 3.7 ± 2.5
2.9 ± 2.9 3.1 ± 2.7 3.2 ± 2.5
.28 .01b .06
59.5 ± 90.1 323.8 ± 256.6 302.5 ± 216.8
125.7 ± 108.8 349.9 ± 289.1 323.3 ± 293.6
<.001b .27 .46
± ± ± ±
<.001b <.001b .01b <.001b
36.8 50.3 36.5 52.2
± ± ± ±
19.9 35.8 31.9 34.2
23.7 35.0 27.7 37.2
17.7 30.1 33.2 28.0
P Value
a
ASA, American Society of Anesthesiologists; BMI, body mass index; MMEs, morphine milligram equivalents; OA, osteoarthritis; Oxy, oxycodone; POD, postoperative day; TKA, total knee arthroplasty; VAS, visual analog scale. a Chi-square test. b Statistically significant, P < .05.
sensitive to certain painful stimuli [25]. After learning more about these risks in November 2017, our hip and knee service decided to abruptly stop treating patients with the preoperative oxycodone we had long considered standard of care. The purpose of this study is to perform a preliminary quality review to determine whether we should continue to avoid preoperative opioids or revert back to our prior PMA protocol that incorporated their regular use. Materials and Methods This study was designed as a retrospective case-controlled quality improvement analysis. Institutional review board approval was obtained before any data collection or data analysis being performed. Study Population The study group consisted of 275 consecutive patients who underwent elective, primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) by 1 of 3 fellowship-trained arthroplasty surgeons at our urban, academic medical center after we abruptly stopped using preemptive oxycodone on November 13, 2017. The study group was compared to a control group consisting of a matched cohort of 275 patients who underwent surgery just before November 13, 2017, at the same academic medical center using identical perioperative protocols with the exception of the single dose of preemptive oxycodone. Groups were matched for age, gender, body mass index, American Society of Anesthesiologists score, anesthesia type (spinal vs general, utilization of adductor canal block), preoperative diagnosis (osteoarthritis vs other), procedure (THA vs TKA), and incision-to-closure operative time (Table 1). Perioperative Pain Management Protocol Our institution used a perioperative pain management protocol we considered to be consistent with standard of care for patients
Table 2 Perioperative Pain Management Protocol for THA and TKA. Preemptive Multimodal Analgesia (Preoperative Holding Area) (1) Celecoxib 400 mg (PO), if normal renal function celecoxib 200 mg (PO), if creatinine 1.1-1.3 mg/dL hold celecoxib if renal insufficiency (creatinine 1.4 mg/dL) (2) Gabapentin 300 mg (PO) (3) Acetaminophen 975 mg (PO) (4) Extended-release oxycodone HCl 10 mg (PO) for age <70,a 5 mg oxycodone for age 70-80,a hold for age 80 y (5) Ultrasound-guided adductor canal block, 0.5% ropivacaine 15 mL (TKA only) Intraoperative Multimodal Analgesia (Operating Room) (1) Spinal anesthesia (when not contraindicated) (2) Periarticular injection 60 mL 0.25% bupivacaine Postoperative Multimodal Analgesia (Recovery Room/Orthopedic Floor) (1) Ketorolac 30 mg every 6 h 4 doses (IV), if normal renal function ketorolac 15 mg every 6 h 4 doses (IV), if creatinine 1.1-1.3 mg/dL hold ketorolac if renal insufficiency (creatinine 1.4 mg/dL) (2) Celecoxib 200 mg every 12 h (PO), starting 24h postoperatively hold celecoxib if renal insufficiency (creatinine 1.4 mg/dL) (3) Acetaminophen 975 mg every 8 h (PO) (4) Oxycodone HCl extended release 10 mg every 12 h 3 doses (PO), hold for age 80 y (5) Oxycodone 5 mg every 3 h (PO), as needed for moderate pain (6) Oxycodone 10 mg every 3 h (PO), as needed for severe pain (7) Hydromorphone 0.4 mg every 3 h (IV), as needed for breakthrough IV, intravenous; PO, per oral; TKA, total knee arthroplasty; THA, total hip arthroplasty. a Discontinued on November 13, 2017.
H.J. Cooper et al. / The Journal of Arthroplasty xxx (2019) 1e6 Table 3 Patient Demographics and Clinical Outcomes of the THA Cohort. Variables Age Gender Female (%) Male (%) BMI ASA Preoperative diagnosis OA (%) Other (%) Length of stay Anesthesia type Spinal (%) General (%) Operative time (min) Discharge disposition Home (%) Outside (%) VAS pain scores (1-10) POD0 POD1 POD2 Number of feet walked POD0 POD1 POD2 Morphine equivalent (mg) POD0 POD1 POD2 Morphine equivalents/d
THA With Oxy (N ¼ 160)
THA Without Oxy (N ¼ 160)
Table 4 Patient Demographics and Clinical Outcomes of the TKA Cohort. P Value
60.2 ± 11.3
62.2 ± 13.4
.14
83 (51.9%) 77 (48.1%) 28.2 ± 5.8 2.1 ± 0.53
89 (55.6%) 71 (44.4%) 27.9 ± 5.3 2.2 ± 0.54
.34 .58 .25
133 (83.1%) 27 (16.9%) 2.2 ± 0.95
135 (84.4%) 25 (15.6%) 2.1 ± 1.3
.67 .70
141 (88.1%) 19 (11.9%) 108.0 ± 26.0
143 (89.4%) 17 (10.6%) 107.8 ± 26.4
.63 .95
140 (87.5%) 20 (12.5%)
136 (85.0%) 24 (15.0%)
.34
3.4 ± 3.0 3.7 ± 2.7 3.4 ± 2.6
2.7 ± 2.8 2.6 ± 2.6 2.6 ± 2.5
60.6 ± 98.2 362.0 ± 279.4 294.7 ± 203.0
138.6 ± 116.9 386.0 ± 310.1 344.6 ± 325.8
<.0001a .48a .19
± ± ± ±
<.0001a <.0001a .001a <.0001a
40.67 53.96 42.22 56.55
± ± ± ±
19.61 39.71 38.34 37.49
23.35 32.81 23.15 35.5
18.43 30.52 37.34 30.4
3
.041a .0006a .045a
ASA, American Society of Anesthesiologists; BMI, body mass index; OA, osteoarthritis; oxy, oxycodone; POD, postoperative day; THA, total hip arthroplasty; VAS, visual analog scale. a Statistically significant, P < .05.
undergoing elective hip and knee arthroplasty, incorporating a multimodal approach to pain control with goals of controlling pain, limiting opioids, and minimizing side effects to allow for rapid mobilization (Table 2). This protocol remained consistent over the study period, except for elimination of preoperative oxycodone in November 2017 for reasons described above. The majority of patients underwent spinal anesthesia, with the majority of TKA patients receiving a preoperative adductor canal block administered by a regional anesthesiologist under ultrasonographic guidance. Almost all patients received a periarticular injection with 60 cc of 0.25% bupivacaine (Table 1). Outcome Measures Primary outcome measures of postoperative pain included (1) visual analog scale (VAS) scores on postoperative day (POD) 0, POD1, and POD2, and (2) total opioid utilization during the hospital stay. Opioid conversion factors were used to convert various opioids to morphine equivalents [26]. Secondary outcome measures were LOS, discharge disposition, and the number of feet walked with physical therapy on POD1 and POD2. Outcomes were compared for the overall combined cohort of all total joint patients, as well as for subgroups of patients undergoing only THA and those undergoing only TKA. Statistical Analysis Descriptive statistics including mean, range, and standard deviation were performed to report patient demographics. Paired
Variables Age Gender Female (%) Male (%) BMI ASA Preoperative diagnosis OA (%) Other (%) Length of stay Anesthesia type Spinal (%) General (%) Adductor canal block Periarticular injection Operative time (min) Intraoperative MMEs Discharge disposition Home (%) Outside (%) VAS pain scores (1-10) POD0 POD1 POD2 Number of feet walked POD0 POD1 POD2 Morphine equivalents (mg) POD0 POD1 POD2 Morphine equivalents/d
TKA With Oxy (N ¼ 115)
TKA Without Oxy (N ¼ 115)
67.2 ± 10.6
66.4 ± 10.9
P Value .57
82 (71.3%) 33 (28.7%) 31.5 ± 10.4 2.2 ± 0.47
77 (67.0%) 38 (33.0%) 30.7 ± 5.7 2.3 ± 0.5
.30a .47 .41
109 (94.8%) 6 (5.2%) 2.6 ± 1.0
108 (93.9%) 7 (6.1%) 2.6 ± 1.6
.67a .63
103 (88.0%) 14 (12.0%) 75 (65.21%) 112 (97.4%) 119.3 ± 20.4 10.0 ± 8.4
102 (88.7%) 113 (11.3%) 82 (71.3%) 109 (94.8%) 118.8 ± 22.4 8.6 ± 9.3
.78a .17a .08a .88 .24
92 (80.0%) 23 (20.0%)
97 (84.4%) 18 (15.6%)
.24a,b
2.9 ± 2.9 3.7 ± 2.4 4.1 ± 2.4
3.2 ± 2.9 3.8 ± 2.7 3.8 ± 2.3
57.9 ± 70.0 270.1 ± 194.0 314.7 ± 231.0
98.2 ± 83.5 297.7 ± 247.8 301.4 ± 256.9
31.5 45.6 31.1 46.2
± ± ± ±
19.1 29.8 23.3 28.0
24.3 37.9 32.0 39.7
± ± ± ±
16.7 29.5 28.2 24.2
.42 .76 .49 .005b .38 .73 <.003b .049b .82 .06
ASA, American Society of Anesthesiologists; BMI, body mass index; MMEs, morphine milligram equivalents; OA, osteoarthritis; oxy, oxycodone; POD, postoperative day; TKA, total knee arthroplasty; VAS, visual analog scale. a Chi-square test. b Statistically significant, P < .05.
t-tests were used for continuous variables to determine statistical significance between groups, while chi-square tests were used for categorical variables. Data analyses were performed using SPSS for Windows statistical software (version 18.0; SPSS, Chicago, IL). P < .05 was considered statistically significant.
Source of Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Results Combined Cohort (THA þ TKA) When compared to the control group that received preemptive oxycodone, the study group that did not receive preemptive opioids reported significantly lower VAS pain scores on POD1 (3.1 vs 3.7, P ¼ .001; Table 1). In addition, the study group consumed significantly fewer morphine equivalents over their hospital stay (37.2 mg per day vs 52.2 mg per day, P < .0001). While there was no difference in LOS or discharge disposition between groups, the study group that avoided preemptive preoperative opioids walked significantly further with physical therapy on POD0 (125.7’ vs 59.5’, P ¼ .001).
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Table 5 Preoperative PMA Regimens Published in Major Orthopedic Journals Recommending Preoperative Administration of Extended-Release Opioids Before Total Joint Arthroplasty. Study
Year
Journal
Preoperative Opioid Dose
Berger et al [8] Hebl et al [9] Berger et al [10] Parvataneni et al [11]
2004 2005 2005 2007
J Arthroplasty J Bone Joint Surg Am J Arthroplasty J Arthroplasty
OxyContin OxyContin OxyContin OxyContin (>70 y) OxyContin (<70 y) OxyContin OxyContin
10 20 10 10
OxyContin OxyContin (>70 y) OxyContin (<70 y) OxyContin
10 mg 10 mg
Hebl et al [12] Berger et al [13]
2008 2009
Beaupre et al [14] Kelley et al [15]
2012 2013
Rodriguez et al [16]
2014
Pulos and Sheth [17] Dalury [18]
2014 2016
Reg Anesth Pain Med Clin Orthop Relat Res Sci World J J Arthroplasty
Clin Orthop Relat Res Ann Orthop Rheumatol Arthroplasty Today
mg mg mg mg
20 mg 20 mg 10 mg
20 mg 20 mg
MS Contin 15 mg OxyContin 10 mg (M > 70 y) OxyContin 20 mg (M < 70 y)
PMA, preemptive multimodal analgesia.
THA Cohort When compared to the control group of patients undergoing THA (Table 3) that received preoperative oxycodone, the study group that did not receive preemptive opioids reported significantly lower VAS pain scores throughout their hospital stay (POD0: 2.7 vs 3.7, P ¼ .041; POD1: 2.6 vs 3.7, P ¼ .0006; POD2: 2.6 vs 3.4, P ¼ .045). In addition, the study group consumed significantly fewer morphine equivalents over their hospital stay on every postoperative day, and when calculated as morphine equivalents per day (35.5 mg vs 56.6 mg; P < .0001). While there was no difference in LOS or discharge disposition between THA subgroups, the study group that avoided preemptive preoperative opioids walked significantly further with physical therapy on POD0 (138.6’ vs 60.6’; P ¼ .001). TKA Cohort When separating out the TKA subgroup, there were fewer statistically significant differences between the group of patients undergoing TKA that received preemptive oxycodone and the group that did not, yet several notable differences remained. The group that did not receive preemptive opioids consumed statistically significantly fewer morphine equivalents on POD0 (24.3 mg vs 31.5 mg, P < .003) and POD1 (37.9 mg vs 45.6 mg; P ¼ .049) and also walked further with physical therapy on POD0 (98.2’ vs 57.9’, P ¼ .008; Table 4). There were no statistically significant differences in terms of VAS pain scores, LOS, or discharge disposition. Discussion This retrospective analysis found convincing evidence that use of preoperative preemptive opioids, a protocol that has been widely adopted at many orthopedic centers in the United States despite minimal evidence to support its use, was associated with higher pain scores, worse early postoperative function, and greater opioid consumption in the immediate postoperative period following
elective total joint arthroplasty. The findings were most significant in patients undergoing THA, with less of a negative association in patients undergoing TKA. These findings may seem counterintuitive and contrary to many well-designed studies that suggest preoperative PMA protocols decrease postoperative pain and allow for earlier mobilization. However, to our knowledge, no prior studies have isolated the influence of opioids from the remaining multimodal agents used such as selective COX-2 inhibitors, gabapentinoids, acetaminophen, and preoperative nerve blocks. In contrast, preoperative administration of both COX-2 inhibitors alone [27e29] and gabapentinoids alone [24,30] has been associated with decreased postoperative pain following joint arthroplasty. Therefore, positive outcomes for PMA may have resulted more from nonopioid analgesics. Although numerous publications have advocated for the use of preoperative long-acting opioids since at least 2004 (Table 5), this may be the first study to isolate opioids from the other preemptive analgesic modalities and draw their use into question. The findings presented here are most likely multifactorial, but opioid-induced hyperalgesia may play a large role. Most orthopedic surgeons are familiar with opioid tolerance, which occurs when patients who have been taking opioids chronically require increasing doses to achieve the same analgesic effect. OIH is a distinctly different entity, and one that may be less familiar to orthopedic surgeons. It is defined as increased sensitivity to painful stimuli as a result of opioid use [25]. Our understanding of OIH during the perioperative period is evolving, but several studies outside of the orthopedic literature have demonstrated higher levels of pain and increased opioid requirements in patients exposed to high doses of intraoperative opioids. To date, evidence of acute perioperative OIH from outside the orthopedic literature involves high intraoperative doses of fentanyl or remifentanil [31e36]. Yet, even with this limited evidence, Hayhurst and Durieux [25] recommend that “OIH (or acute tolerance) can occur within the perioperative period and it should be considered when opioids are administered during surgery.” It is unclear why the patients undergoing THA who did not receive preemptive oxycodone consumed significantly fewer morphine milligram equivalents postoperatively and maintained better VAS scores, while patients undergoing TKA did not. At present, the ability to draw conclusions about these differences is limited by the study’s retrospective methodology. Patient’s preoperative opioid usage, for example, was unfortunately not well documented and a potential confounder and weakness due to the retrospective nature of the study. While it is reasonable to argue that the differences in VAS scores, even when statistically significant, may not necessarily reach clinical significance, the dramatic concomitant decrease in postoperative opioid consumptions, particularly in the THA subgroup, is worth considering. Our data have the potential to be immediately impactful, as the United States is in the midst of an opioid epidemic. An estimated 2 million people were addicted to prescription opioids in 2015 [37]. The number of opioids prescribed in the United States quadrupled from 1999 to 2010 [38], due largely to an increase in the use of opioids to treat noncancer pain [39,40]. Of all American medical providers, orthopedic surgeons are among the most frequent prescribers of opioid medications, prescribing 7.7% of all opioid prescriptions filled by outpatient retail pharmacies in 2009 [41] despite making up less than 0.05% of all providers [42]. Among patients who are opioid naïve the day of surgery, approximately 8% of TKA and 4% of THA patients will continue using opioids at 6 months [43]. Our data suggest that offering patients less opioids immediately before surgery is associated with less pain and a further reduction in opioid use during the early postoperative
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period. While clearly promising, this deserves further investigation in prospective, randomized studies. We note several limitations to our methodology. This study represents the experience of a single center over a relatively short period of time; although the magnitude of the differences we observed was statistically significant, it is possible these may not generalize to other institutions and patient populations. Second, we acknowledge the inherent limitations of the study’s retrospective methodology. Third, the study and control groups underwent total joint arthroplasty at 2 consecutive intervals, not simultaneously. While the time between these intervals was quite short, it is possible other temporal variables may have changed that we were not able to account for that were responsible for the differences seen. In the authors’ opinion, however, the groups were so closely separated chronologically, with no other intentional changes in perioperative protocols, that chronological bias is unlikely to have played a significant role. Fourth, chronic preoperative opioid consumption patterns were not taken into account in this study. If a patient were a chronic opioid user before surgery, it is conceivable that administration or withholding of preemptive oxycodone may affect that patient differently than an opioid-naïve patient. Due to the retrospective nature of this study, we were not able to take such patient history factors into account. Therefore, the conclusions of this study may not be applicable to chronic opioid users where withholding preemptive opioids could potentially even be detrimental to their early recovery. Finally, it is important to note that our study demonstrates a statistical association between preoperative oxycodone and increased postoperative pain and does not demonstrate causation. Conclusions In summary, we demonstrate that preoperative PMA incorporating an opioid is associated with significantly higher VAS pain scores, greater postoperative opioid requirements, and shorter postoperative ambulation distances when compared to preoperative PMA without opioids in patients undergoing primary, elective total joint arthroplasty. The differences appear to be more dramatic in THA patients, with no clear benefit to giving preemptive opioids in TKA patients. Based on our data, we recommend that orthopedic surgeons (1) consider eliminating preoperative opioids from PMA protocols pending further studies and (2) study this important issue further with higher-quality, prospective, randomized studies that follow these patients over longer periods. Acknowledgments The authors would like to thank Ari Berg, MD, and Emma Jennings, BS, for their invaluable assistance with data collection. References [1] Barlow T, Griffin D, Barlow D, Realpe A. Patients' decision making in total knee arthroplasty: a systematic review of qualitative research. Bone Joint Res 2015;4:163e9. [2] Lamplot JD, Wagner ER, Manning DW. Multimodal pain management in total knee arthroplasty: a prospective randomized controlled trial. J Arthroplasty 2014;29:329e34. [3] Vendittoli PA, Makinen P, Drolet P, Lavigne M, Fallaha M, Guertin MC, et al. A multimodal analgesia protocol for total knee arthroplasty. A randomized, controlled study. J Bone Joint Surg Am 2006;88:282e9. [4] Maheshwari AV, Blum YC, Shekhar L, Ranawat AS, Ranawat CS. Multimodal pain management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center. Clin Orthop Relat Res 2009;467:1418e23. [5] Indelli PF, Grant SA, Nielsen K, Vail TP. Regional anesthesia in hip surgery. Clin Orthop Relat Res 2005:250e5. [6] Ranawat CS, Ranawat AS, Mehta A. Total knee arthroplasty rehabilitation protocol: what makes the difference? J Arthroplasty 2003;18(3 Suppl 1):27e30.
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Differential opioid tolerance and opioid-induced hyperalgesia. Anesthesiology 2016;124:483e8. [26] National Center for Injury Prevention and Control. CDC compilation of benzodiazepines, muscle relaxants, stimulants, zolpidem, and opioid analgesics with oral morphine milligram equivalent conversion factors, 2016 version. Atlanta, GA: Centers for Disease Control and Prevention; 2016. http://www. pdmpassist.org/pdf/BJA_performance_measure_aid_MME_conversion.pdf [accessed 09.03.18]. [27] Buvanendran A, Kroin JS, Tuman KJ, Lubenow TR, Elmofty D, Moric M, et al. Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial. JAMA 2003;290:2411e8. [28] Lin J, Zhang L, Yang H. Perioperative administration of selective cyclooxygenase-2 inhibitors for postoperative pain management in patients after total knee arthroplasty. J Arthroplasty 2013;28:207e213.e2. [29] Chen J, Zhu W, Zhang Z, Zhu L, Zhang W, DU Y. Efficacy of celecoxib for acute pain management following total hip arthroplasty in elderly patients: a prospective, randomized, placebo-control trial. Exp Ther Med 2015;10: 737e42. [30] Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg 2010;110: 199e207. [31] Salengros JC, Huybrechts I, Ducart A, Faraoni D, Marsala C, Barvais L, et al. Different anesthetic techniques associated with different incidences of chronic post-thoracotomy pain: low-dose remifentanil plus presurgical epidural analgesia is preferable to high-dose remifentanil with postsurgical epidural analgesia. J Cardiothorac Vasc Anesth 2010;24:608e16.
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Preemptive Analgesia With Oxycodone Is Associated With More Pain Following Total Joint Arthroplasty H. John Cooper, MD a, *, Akshay Lakra, MD a, Robert B. Maniker, MD b, Thomas R. Hickernell, MD a, Roshan P. Shah, MD a, Jeffrey A. Geller, MD a a b
Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY Department of Anesthesiology, Columbia University Medical Center, New York, NY
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 June 2018 Received in revised form 12 July 2019 Accepted 17 July 2019 Available online xxx
Background: Preemptive multimodal analgesia (PMA) is a commonly used technique to control pain following total joint arthroplasty. PMA protocols use multiple analgesics immediately preoperatively to prevent central sensitization and amplification of pain during surgery. While benefits of some individual components of a PMA protocol have been established, there are little data to support inclusion or exclusion of opioids in this context. Methods: This is a retrospective cohort study of 550 patients undergoing elective, primary total joint arthroplasty at a single institution using a standardized preoperative perioperative protocol. Two hundred seventy-five patients received oxycodone in addition to a standard multimodal preoperative analgesia regimen just before surgery and were compared to a matched cohort of 275 patients who received the standard regimen alone. Outcome measures included inpatient visual analog scale pain scores, inpatient opioid consumption, length of stay, and ambulation distance with physical therapy. Results: Patients who received opioids in preoperative holding reported significantly greater visual analog scale pain scores on postoperative day 1 (3.7 vs 3.1; P ¼ .01), when compared to those who did not. These patients also walked shorter distances on postoperative day 0 (59.5’ vs 125.7’; P < .001) and consumed greater morphine equivalents per hospital day over the course of their hospital stay (52.2 vs 37.2 mg; P < .001). These differences remained significant when stratified by procedure, total knee arthroplasty or total hip arthroplasty. Differences in pain and function between groups were more pronounced in patients undergoing total hip arthroplasty than those undergoing total knee arthroplasty. Conclusion: Total joint patients who were given preemptive opioids immediately before surgery experienced more pain, consumed more postoperative opioids, and exhibited impaired early function as compared to those who were not given preemptive opioids. Orthopedic surgeons should reconsider routine use of preemptive opioids in this context. © 2019 Elsevier Inc. All rights reserved.
Keywords: opioid-induced hyperalgesia oxycodone pain preemptive analgesia total hip arthroplasty total knee arthroplasty
Ethical Review Committee Statement: This study was approved by our institutional review board (IRB-AAAR5714) and conducted in accordance with the ethical standards in the 1964 Declaration of Helsinki. This work was performed in the Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY. One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.arth.2019.07.021. * Reprint requests: H. John Cooper, MD, Department of Orthopedic Surgery, Columbia University Medical Center, 622 W 168th St, PH-11, New York, NY 10032. https://doi.org/10.1016/j.arth.2019.07.021 0883-5403/© 2019 Elsevier Inc. All rights reserved.
Pain following total joint arthroplasty is a significant concern for our patients [1]. Poorly controlled postoperative pain causes unnecessary discomfort and dissatisfaction, limits recovery and rehabilitation, increases cost and length of stay (LOS), and leads to worse outcomes [2e6]. Multimodal analgesia is the combination of relatively low doses of multiple different medication classes in order to maximize analgesia while minimizing side effects. Preemptive multimodal analgesia (PMA) is a commonly used method of addressing postoperative pain, wherein multimodal analgesia is initiated before the painful stimulus with the goals of preventing central sensitization and amplification of pain during surgery [7]. Preoperative PMA was introduced and widely adopted in centers performing total joint arthroplasty over the past 15 years [8e18],
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and in conjunction with evolving regional anesthesia techniques and local periarticular injections, has been effective in decreasing the overall use of opioids, decreasing postoperative pain, decreasing LOS, and facilitating more rapid mobilization [8e10,13,16,19,20]. Specific preoperative PMA regimens vary throughout the literature, but typically consist of a selective COX-2 inhibitor [8e10,12e16,18,19,21e23] and an extended-release opioid [8e10,12e19], with some centers adding other modalities such as acetaminophen [17,21e23], gabapentinoids [12,17,19,21e24], or peripheral nerve blocks [9,12,19] to this “preoperative cocktail.” The conceptual framework of preoperative PMA makes sense intuitively, aiding its widespread adoption across many orthopedic centers without rigorous analysis of the individual components of the preoperative regimen. While several individual medications in the multimodal analgesic approach have been studied in isolation, others have not, leaving open the possibility that some components of the preoperative PMA regimen may not be helpful and may actually be counterproductive in controlling postoperative pain. Of all pharmacologic options for preemptive analgesia, opioids are of particular concern for many reasons. Opioids pose risks of acute and chronic tolerance, dependence, diversion, and opioidinduced hyperalgesia (OIH). Briefly, OIH is a state of nociceptive sensitization caused by (even brief) exposure to opioids, characterized by a paradoxical response wherein patients become more
Table 1 Patient Demographics and Clinical Outcomes. Variables Age Gender Female (%) Male (%) BMI ASA Preoperative diagnosis OA (%) Other (%) Length of stay Anesthesia type Spinal (%) General (%) Adductor canal block (for TKA only) Periarticular injection Operative time (min) Intraoperative MMEs Discharge disposition Home (%) Outside (%) VAS pain scores (1-10) POD0 POD1 POD2 Number of feet walked POD0 POD1 POD2 Morphine equivalents (mg) POD0 POD1 POD2 Morphine equivalents/d
Oxy (N ¼ 275)
Without Oxy (N ¼ 275)
63.1 ± 11.5
64.0 ± 12.6
.40
165 (60%) 110 (40%) 29.6 ± 8.2 2.2 ± 0.51
166 (60.4%) 109 (39.6%) 29.0 ± 5.6 2.2 ± 0.52
.40a .36 .16
242 (88%) 33 (12%) 2.3 ± 0.99
243 (88.4%) 32 (11.6%) 2.3 ± 1.4
.85a .94
244 (88.7%) 31 (11.3%) 75 (65%)
245 (89.1%) 30 (10.9%) 82 (71%)
.85 .17a
268 (97.5%) 112.7 ± 24.4 9.4 ± 7.9
263 (95.6%) 112.4 ± 25.4 8.5 ± 9.0
.14a .90 .21
232 (84.4%) 43 (15.6%)
233 (84.7%) 42 (15.3%)
.87a,b
3.2 ± 2.9 3.7 ± 2.6 3.7 ± 2.5
2.9 ± 2.9 3.1 ± 2.7 3.2 ± 2.5
.28 .01b .06
59.5 ± 90.1 323.8 ± 256.6 302.5 ± 216.8
125.7 ± 108.8 349.9 ± 289.1 323.3 ± 293.6
<.001b .27 .46
± ± ± ±
<.001b <.001b .01b <.001b
36.8 50.3 36.5 52.2
± ± ± ±
19.9 35.8 31.9 34.2
23.7 35.0 27.7 37.2
17.7 30.1 33.2 28.0
P Value
a
ASA, American Society of Anesthesiologists; BMI, body mass index; MMEs, morphine milligram equivalents; OA, osteoarthritis; Oxy, oxycodone; POD, postoperative day; TKA, total knee arthroplasty; VAS, visual analog scale. a Chi-square test. b Statistically significant, P < .05.
sensitive to certain painful stimuli [25]. After learning more about these risks in November 2017, our hip and knee service decided to abruptly stop treating patients with the preoperative oxycodone we had long considered standard of care. The purpose of this study is to perform a preliminary quality review to determine whether we should continue to avoid preoperative opioids or revert back to our prior PMA protocol that incorporated their regular use. Materials and Methods This study was designed as a retrospective case-controlled quality improvement analysis. Institutional review board approval was obtained before any data collection or data analysis being performed. Study Population The study group consisted of 275 consecutive patients who underwent elective, primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) by 1 of 3 fellowship-trained arthroplasty surgeons at our urban, academic medical center after we abruptly stopped using preemptive oxycodone on November 13, 2017. The study group was compared to a control group consisting of a matched cohort of 275 patients who underwent surgery just before November 13, 2017, at the same academic medical center using identical perioperative protocols with the exception of the single dose of preemptive oxycodone. Groups were matched for age, gender, body mass index, American Society of Anesthesiologists score, anesthesia type (spinal vs general, utilization of adductor canal block), preoperative diagnosis (osteoarthritis vs other), procedure (THA vs TKA), and incision-to-closure operative time (Table 1). Perioperative Pain Management Protocol Our institution used a perioperative pain management protocol we considered to be consistent with standard of care for patients
Table 2 Perioperative Pain Management Protocol for THA and TKA. Preemptive Multimodal Analgesia (Preoperative Holding Area) (1) Celecoxib 400 mg (PO), if normal renal function celecoxib 200 mg (PO), if creatinine 1.1-1.3 mg/dL hold celecoxib if renal insufficiency (creatinine 1.4 mg/dL) (2) Gabapentin 300 mg (PO) (3) Acetaminophen 975 mg (PO) (4) Extended-release oxycodone HCl 10 mg (PO) for age <70,a 5 mg oxycodone for age 70-80,a hold for age 80 y (5) Ultrasound-guided adductor canal block, 0.5% ropivacaine 15 mL (TKA only) Intraoperative Multimodal Analgesia (Operating Room) (1) Spinal anesthesia (when not contraindicated) (2) Periarticular injection 60 mL 0.25% bupivacaine Postoperative Multimodal Analgesia (Recovery Room/Orthopedic Floor) (1) Ketorolac 30 mg every 6 h 4 doses (IV), if normal renal function ketorolac 15 mg every 6 h 4 doses (IV), if creatinine 1.1-1.3 mg/dL hold ketorolac if renal insufficiency (creatinine 1.4 mg/dL) (2) Celecoxib 200 mg every 12 h (PO), starting 24h postoperatively hold celecoxib if renal insufficiency (creatinine 1.4 mg/dL) (3) Acetaminophen 975 mg every 8 h (PO) (4) Oxycodone HCl extended release 10 mg every 12 h 3 doses (PO), hold for age 80 y (5) Oxycodone 5 mg every 3 h (PO), as needed for moderate pain (6) Oxycodone 10 mg every 3 h (PO), as needed for severe pain (7) Hydromorphone 0.4 mg every 3 h (IV), as needed for breakthrough IV, intravenous; PO, per oral; TKA, total knee arthroplasty; THA, total hip arthroplasty. a Discontinued on November 13, 2017.
H.J. Cooper et al. / The Journal of Arthroplasty xxx (2019) 1e6 Table 3 Patient Demographics and Clinical Outcomes of the THA Cohort. Variables Age Gender Female (%) Male (%) BMI ASA Preoperative diagnosis OA (%) Other (%) Length of stay Anesthesia type Spinal (%) General (%) Operative time (min) Discharge disposition Home (%) Outside (%) VAS pain scores (1-10) POD0 POD1 POD2 Number of feet walked POD0 POD1 POD2 Morphine equivalent (mg) POD0 POD1 POD2 Morphine equivalents/d
THA With Oxy (N ¼ 160)
THA Without Oxy (N ¼ 160)
Table 4 Patient Demographics and Clinical Outcomes of the TKA Cohort. P Value
60.2 ± 11.3
62.2 ± 13.4
.14
83 (51.9%) 77 (48.1%) 28.2 ± 5.8 2.1 ± 0.53
89 (55.6%) 71 (44.4%) 27.9 ± 5.3 2.2 ± 0.54
.34 .58 .25
133 (83.1%) 27 (16.9%) 2.2 ± 0.95
135 (84.4%) 25 (15.6%) 2.1 ± 1.3
.67 .70
141 (88.1%) 19 (11.9%) 108.0 ± 26.0
143 (89.4%) 17 (10.6%) 107.8 ± 26.4
.63 .95
140 (87.5%) 20 (12.5%)
136 (85.0%) 24 (15.0%)
.34
3.4 ± 3.0 3.7 ± 2.7 3.4 ± 2.6
2.7 ± 2.8 2.6 ± 2.6 2.6 ± 2.5
60.6 ± 98.2 362.0 ± 279.4 294.7 ± 203.0
138.6 ± 116.9 386.0 ± 310.1 344.6 ± 325.8
<.0001a .48a .19
± ± ± ±
<.0001a <.0001a .001a <.0001a
40.67 53.96 42.22 56.55
± ± ± ±
19.61 39.71 38.34 37.49
23.35 32.81 23.15 35.5
18.43 30.52 37.34 30.4
3
.041a .0006a .045a
ASA, American Society of Anesthesiologists; BMI, body mass index; OA, osteoarthritis; oxy, oxycodone; POD, postoperative day; THA, total hip arthroplasty; VAS, visual analog scale. a Statistically significant, P < .05.
undergoing elective hip and knee arthroplasty, incorporating a multimodal approach to pain control with goals of controlling pain, limiting opioids, and minimizing side effects to allow for rapid mobilization (Table 2). This protocol remained consistent over the study period, except for elimination of preoperative oxycodone in November 2017 for reasons described above. The majority of patients underwent spinal anesthesia, with the majority of TKA patients receiving a preoperative adductor canal block administered by a regional anesthesiologist under ultrasonographic guidance. Almost all patients received a periarticular injection with 60 cc of 0.25% bupivacaine (Table 1). Outcome Measures Primary outcome measures of postoperative pain included (1) visual analog scale (VAS) scores on postoperative day (POD) 0, POD1, and POD2, and (2) total opioid utilization during the hospital stay. Opioid conversion factors were used to convert various opioids to morphine equivalents [26]. Secondary outcome measures were LOS, discharge disposition, and the number of feet walked with physical therapy on POD1 and POD2. Outcomes were compared for the overall combined cohort of all total joint patients, as well as for subgroups of patients undergoing only THA and those undergoing only TKA. Statistical Analysis Descriptive statistics including mean, range, and standard deviation were performed to report patient demographics. Paired
Variables Age Gender Female (%) Male (%) BMI ASA Preoperative diagnosis OA (%) Other (%) Length of stay Anesthesia type Spinal (%) General (%) Adductor canal block Periarticular injection Operative time (min) Intraoperative MMEs Discharge disposition Home (%) Outside (%) VAS pain scores (1-10) POD0 POD1 POD2 Number of feet walked POD0 POD1 POD2 Morphine equivalents (mg) POD0 POD1 POD2 Morphine equivalents/d
TKA With Oxy (N ¼ 115)
TKA Without Oxy (N ¼ 115)
67.2 ± 10.6
66.4 ± 10.9
P Value .57
82 (71.3%) 33 (28.7%) 31.5 ± 10.4 2.2 ± 0.47
77 (67.0%) 38 (33.0%) 30.7 ± 5.7 2.3 ± 0.5
.30a .47 .41
109 (94.8%) 6 (5.2%) 2.6 ± 1.0
108 (93.9%) 7 (6.1%) 2.6 ± 1.6
.67a .63
103 (88.0%) 14 (12.0%) 75 (65.21%) 112 (97.4%) 119.3 ± 20.4 10.0 ± 8.4
102 (88.7%) 113 (11.3%) 82 (71.3%) 109 (94.8%) 118.8 ± 22.4 8.6 ± 9.3
.78a .17a .08a .88 .24
92 (80.0%) 23 (20.0%)
97 (84.4%) 18 (15.6%)
.24a,b
2.9 ± 2.9 3.7 ± 2.4 4.1 ± 2.4
3.2 ± 2.9 3.8 ± 2.7 3.8 ± 2.3
57.9 ± 70.0 270.1 ± 194.0 314.7 ± 231.0
98.2 ± 83.5 297.7 ± 247.8 301.4 ± 256.9
31.5 45.6 31.1 46.2
± ± ± ±
19.1 29.8 23.3 28.0
24.3 37.9 32.0 39.7
± ± ± ±
16.7 29.5 28.2 24.2
.42 .76 .49 .005b .38 .73 <.003b .049b .82 .06
ASA, American Society of Anesthesiologists; BMI, body mass index; MMEs, morphine milligram equivalents; OA, osteoarthritis; oxy, oxycodone; POD, postoperative day; TKA, total knee arthroplasty; VAS, visual analog scale. a Chi-square test. b Statistically significant, P < .05.
t-tests were used for continuous variables to determine statistical significance between groups, while chi-square tests were used for categorical variables. Data analyses were performed using SPSS for Windows statistical software (version 18.0; SPSS, Chicago, IL). P < .05 was considered statistically significant.
Source of Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Results Combined Cohort (THA þ TKA) When compared to the control group that received preemptive oxycodone, the study group that did not receive preemptive opioids reported significantly lower VAS pain scores on POD1 (3.1 vs 3.7, P ¼ .001; Table 1). In addition, the study group consumed significantly fewer morphine equivalents over their hospital stay (37.2 mg per day vs 52.2 mg per day, P < .0001). While there was no difference in LOS or discharge disposition between groups, the study group that avoided preemptive preoperative opioids walked significantly further with physical therapy on POD0 (125.7’ vs 59.5’, P ¼ .001).
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Table 5 Preoperative PMA Regimens Published in Major Orthopedic Journals Recommending Preoperative Administration of Extended-Release Opioids Before Total Joint Arthroplasty. Study
Year
Journal
Preoperative Opioid Dose
Berger et al [8] Hebl et al [9] Berger et al [10] Parvataneni et al [11]
2004 2005 2005 2007
J Arthroplasty J Bone Joint Surg Am J Arthroplasty J Arthroplasty
OxyContin OxyContin OxyContin OxyContin (>70 y) OxyContin (<70 y) OxyContin OxyContin
10 20 10 10
OxyContin OxyContin (>70 y) OxyContin (<70 y) OxyContin
10 mg 10 mg
Hebl et al [12] Berger et al [13]
2008 2009
Beaupre et al [14] Kelley et al [15]
2012 2013
Rodriguez et al [16]
2014
Pulos and Sheth [17] Dalury [18]
2014 2016
Reg Anesth Pain Med Clin Orthop Relat Res Sci World J J Arthroplasty
Clin Orthop Relat Res Ann Orthop Rheumatol Arthroplasty Today
mg mg mg mg
20 mg 20 mg 10 mg
20 mg 20 mg
MS Contin 15 mg OxyContin 10 mg (M > 70 y) OxyContin 20 mg (M < 70 y)
PMA, preemptive multimodal analgesia.
THA Cohort When compared to the control group of patients undergoing THA (Table 3) that received preoperative oxycodone, the study group that did not receive preemptive opioids reported significantly lower VAS pain scores throughout their hospital stay (POD0: 2.7 vs 3.7, P ¼ .041; POD1: 2.6 vs 3.7, P ¼ .0006; POD2: 2.6 vs 3.4, P ¼ .045). In addition, the study group consumed significantly fewer morphine equivalents over their hospital stay on every postoperative day, and when calculated as morphine equivalents per day (35.5 mg vs 56.6 mg; P < .0001). While there was no difference in LOS or discharge disposition between THA subgroups, the study group that avoided preemptive preoperative opioids walked significantly further with physical therapy on POD0 (138.6’ vs 60.6’; P ¼ .001). TKA Cohort When separating out the TKA subgroup, there were fewer statistically significant differences between the group of patients undergoing TKA that received preemptive oxycodone and the group that did not, yet several notable differences remained. The group that did not receive preemptive opioids consumed statistically significantly fewer morphine equivalents on POD0 (24.3 mg vs 31.5 mg, P < .003) and POD1 (37.9 mg vs 45.6 mg; P ¼ .049) and also walked further with physical therapy on POD0 (98.2’ vs 57.9’, P ¼ .008; Table 4). There were no statistically significant differences in terms of VAS pain scores, LOS, or discharge disposition. Discussion This retrospective analysis found convincing evidence that use of preoperative preemptive opioids, a protocol that has been widely adopted at many orthopedic centers in the United States despite minimal evidence to support its use, was associated with higher pain scores, worse early postoperative function, and greater opioid consumption in the immediate postoperative period following
elective total joint arthroplasty. The findings were most significant in patients undergoing THA, with less of a negative association in patients undergoing TKA. These findings may seem counterintuitive and contrary to many well-designed studies that suggest preoperative PMA protocols decrease postoperative pain and allow for earlier mobilization. However, to our knowledge, no prior studies have isolated the influence of opioids from the remaining multimodal agents used such as selective COX-2 inhibitors, gabapentinoids, acetaminophen, and preoperative nerve blocks. In contrast, preoperative administration of both COX-2 inhibitors alone [27e29] and gabapentinoids alone [24,30] has been associated with decreased postoperative pain following joint arthroplasty. Therefore, positive outcomes for PMA may have resulted more from nonopioid analgesics. Although numerous publications have advocated for the use of preoperative long-acting opioids since at least 2004 (Table 5), this may be the first study to isolate opioids from the other preemptive analgesic modalities and draw their use into question. The findings presented here are most likely multifactorial, but opioid-induced hyperalgesia may play a large role. Most orthopedic surgeons are familiar with opioid tolerance, which occurs when patients who have been taking opioids chronically require increasing doses to achieve the same analgesic effect. OIH is a distinctly different entity, and one that may be less familiar to orthopedic surgeons. It is defined as increased sensitivity to painful stimuli as a result of opioid use [25]. Our understanding of OIH during the perioperative period is evolving, but several studies outside of the orthopedic literature have demonstrated higher levels of pain and increased opioid requirements in patients exposed to high doses of intraoperative opioids. To date, evidence of acute perioperative OIH from outside the orthopedic literature involves high intraoperative doses of fentanyl or remifentanil [31e36]. Yet, even with this limited evidence, Hayhurst and Durieux [25] recommend that “OIH (or acute tolerance) can occur within the perioperative period and it should be considered when opioids are administered during surgery.” It is unclear why the patients undergoing THA who did not receive preemptive oxycodone consumed significantly fewer morphine milligram equivalents postoperatively and maintained better VAS scores, while patients undergoing TKA did not. At present, the ability to draw conclusions about these differences is limited by the study’s retrospective methodology. Patient’s preoperative opioid usage, for example, was unfortunately not well documented and a potential confounder and weakness due to the retrospective nature of the study. While it is reasonable to argue that the differences in VAS scores, even when statistically significant, may not necessarily reach clinical significance, the dramatic concomitant decrease in postoperative opioid consumptions, particularly in the THA subgroup, is worth considering. Our data have the potential to be immediately impactful, as the United States is in the midst of an opioid epidemic. An estimated 2 million people were addicted to prescription opioids in 2015 [37]. The number of opioids prescribed in the United States quadrupled from 1999 to 2010 [38], due largely to an increase in the use of opioids to treat noncancer pain [39,40]. Of all American medical providers, orthopedic surgeons are among the most frequent prescribers of opioid medications, prescribing 7.7% of all opioid prescriptions filled by outpatient retail pharmacies in 2009 [41] despite making up less than 0.05% of all providers [42]. Among patients who are opioid naïve the day of surgery, approximately 8% of TKA and 4% of THA patients will continue using opioids at 6 months [43]. Our data suggest that offering patients less opioids immediately before surgery is associated with less pain and a further reduction in opioid use during the early postoperative
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period. While clearly promising, this deserves further investigation in prospective, randomized studies. We note several limitations to our methodology. This study represents the experience of a single center over a relatively short period of time; although the magnitude of the differences we observed was statistically significant, it is possible these may not generalize to other institutions and patient populations. Second, we acknowledge the inherent limitations of the study’s retrospective methodology. Third, the study and control groups underwent total joint arthroplasty at 2 consecutive intervals, not simultaneously. While the time between these intervals was quite short, it is possible other temporal variables may have changed that we were not able to account for that were responsible for the differences seen. In the authors’ opinion, however, the groups were so closely separated chronologically, with no other intentional changes in perioperative protocols, that chronological bias is unlikely to have played a significant role. Fourth, chronic preoperative opioid consumption patterns were not taken into account in this study. If a patient were a chronic opioid user before surgery, it is conceivable that administration or withholding of preemptive oxycodone may affect that patient differently than an opioid-naïve patient. Due to the retrospective nature of this study, we were not able to take such patient history factors into account. Therefore, the conclusions of this study may not be applicable to chronic opioid users where withholding preemptive opioids could potentially even be detrimental to their early recovery. Finally, it is important to note that our study demonstrates a statistical association between preoperative oxycodone and increased postoperative pain and does not demonstrate causation. Conclusions In summary, we demonstrate that preoperative PMA incorporating an opioid is associated with significantly higher VAS pain scores, greater postoperative opioid requirements, and shorter postoperative ambulation distances when compared to preoperative PMA without opioids in patients undergoing primary, elective total joint arthroplasty. The differences appear to be more dramatic in THA patients, with no clear benefit to giving preemptive opioids in TKA patients. Based on our data, we recommend that orthopedic surgeons (1) consider eliminating preoperative opioids from PMA protocols pending further studies and (2) study this important issue further with higher-quality, prospective, randomized studies that follow these patients over longer periods. Acknowledgments The authors would like to thank Ari Berg, MD, and Emma Jennings, BS, for their invaluable assistance with data collection. References [1] Barlow T, Griffin D, Barlow D, Realpe A. Patients' decision making in total knee arthroplasty: a systematic review of qualitative research. Bone Joint Res 2015;4:163e9. [2] Lamplot JD, Wagner ER, Manning DW. Multimodal pain management in total knee arthroplasty: a prospective randomized controlled trial. J Arthroplasty 2014;29:329e34. [3] Vendittoli PA, Makinen P, Drolet P, Lavigne M, Fallaha M, Guertin MC, et al. A multimodal analgesia protocol for total knee arthroplasty. A randomized, controlled study. J Bone Joint Surg Am 2006;88:282e9. [4] Maheshwari AV, Blum YC, Shekhar L, Ranawat AS, Ranawat CS. Multimodal pain management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center. Clin Orthop Relat Res 2009;467:1418e23. [5] Indelli PF, Grant SA, Nielsen K, Vail TP. Regional anesthesia in hip surgery. Clin Orthop Relat Res 2005:250e5. [6] Ranawat CS, Ranawat AS, Mehta A. Total knee arthroplasty rehabilitation protocol: what makes the difference? J Arthroplasty 2003;18(3 Suppl 1):27e30.
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