Total knee arthroplasty (TKA) is considered one of the most cost-effective and consistently successful orthopaedic surgical procedures designed for patients with end-stage degenerative knee osteoarthritis1,2. This surgical procedure has been shown to specifically restore knee function, improve quality of life, and alleviate osteoarthritic knee pain1,3. In the last few decades, TKA has undergone a stunning evolution in achieving both accuracy and reproducibility in surgical implantation1. Nevertheless, postoperative pain control remains a concerning factor to patients who undergo TKA4,5. Effective postoperative pain control improves patient comfort and mobility and patient-reported outcomes and is associated with decreases in hospital length of stay and the risk of chronic postoperative pain1,6.
Traditionally, opioids have been the pillar of postoperative TKA pain control management1,5. Although they provide potent analgesia, opioids can lead to serious side effects such as respiratory depression, confusion, constipation, nausea, vomiting, pruritus, and urinary retention that may increase hospital length of stay, cost of care, and drug addiction4,6. Currently, the United States is confronting an opioid epidemic, with the World Health Organization reporting that Americans consume 99% of the world’s supply of hydrocodone and 83% of the world’s oxycodone4,7. In order to decrease opioid dependence and minimize opioid-related side effects, alternative postoperative pain management approaches known as multimodal analgesia were introduced in the early 1990s6,8.
Multimodal analgesia combines analgesics from ≥2 drug classes that employ different mechanisms of action, targeting different (i.e., peripheral or central) pain pathways, thus achieving a synergistic effect at lower analgesic doses5,9. Nowadays, non-opioid medications such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly given as multimodal analgesic regimens to enhance pain control and minimize the need for opioids6,10. Both acetaminophen and NSAIDs provide analgesic, antipyretic, and anti-inflammatory relief without opioid-associated effects10–12.
In 2020, Fillingham et al. published systematic reviews11,12 stating the importance of clinical practice guidelines by the American Association of Hip and Knee Surgeons (AAHKS), American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons (AAOS), Hip Society, and The Knee Society for the use of NSAIDs and acetaminophen in patients undergoing total joint arthroplasty (TJA). In the study by Fillingham et al., it was established that postoperative administration of intravenous ketorolac after TJA reduces pain and opioid consumption11. Similarly, the use of oral acetaminophen was found to reduce postoperative pain and opioid consumption, at lower costs than intravenous acetaminophen, following primary TJA12.
Compared with Caucasian patients, Hispanic patients undergoing TKA have been reported to experience higher rates of osteoarthritis and health inequalities such as increased postoperative pain, increased hospital length of stay, higher risk of postoperative infections, and lower levels of satisfaction13–16. With a growing TKA demand, an increased emphasis on improving health optimization for all patients, and especially minority patients, who are at higher risk of experiencing suboptimal outcomes, is imperative14,17. Despite this fact, the efficacy of an immediate postoperative, opioid-free, multimodal analgesic regimen in Hispanic patients who undergo primary TKA has not been reported before. Thus, the purpose of this study was to evaluate if a multimodal analgesia protocol consisting of intravenous ketorolac and oral acetaminophen reduces opioid consumption in Hispanic patients undergoing primary TKA. We hypothesized that Hispanic patients treated with an opioid-sparing multimodal analgesic regimen would consume fewer opioids than those treated with a traditional opioid protocol for inpatient postoperative pain control after undergoing primary TKA.
Materials and Methods
This study was registered at ClinicalTrials.gov (NCT05393414). Following approval from the University of Puerto Rico (UPR) institutional review board (IRB-B0110219), a double-blinded controlled trial of 81 consecutive Hispanic patients who underwent primary TKA from November 2019 to March 2020 was performed. All of the surgical procedures were performed by a single hip and knee replacement fellowship-trained orthopaedic surgeon across 3 hospitals (UPR Hospital, Metropolitan Hospital, and Dr. Ramón Ruiz Arnau University Hospital). The Triathlon Cemented Total Knee System (Stryker) was used in all of the surgical procedures. Inclusion criteria were Hispanic patients undergoing primary TKA; age of >21 years; and an American Society of Anesthesiologists (ASA) classification of I or II. Exclusion criteria were a hypersensitivity to any components of analgesic drugs; impaired renal, cardiac, or hepatic function; baseline serum creatinine level of >1.2 mg/dL; history of gastrointestinal bleeding; neuromuscular deformities; or inability to consent. Informed consent was obtained from all eligible patients after they were informed about the study protocol by the principal investigator and coinvestigators. Subsequently, patients were enrolled in an institutional review board-approved, prospective web-based registry. A random number allocation sequence was generated with SPSS (IBM) and was given to a research assistant, who registered the patients prior to the start of participant enrollment. The research assistant then informed the surgeon of the intervention assigned after informed consent was obtained. Afterwards, participants were randomized into 2 groups and then were analyzed. The analyzed groups were an experimental (opioid-sparing) group (42 patients) and a control (opioid-receiving) group (39 patients). Patients were first informed of the intervention to which they had been randomized when receiving their postoperative pain medication from 6 to 48 hours after the surgical procedure. In accordance with the protocol at our institution, before wound closure, all patients received a single, standard, local periarticular anesthetic infiltration of 8-mg morphine, 30-mg ketorolac, and 10-mL 0.5% bupivacaine. After the surgical procedure, the experimental group received 30-mg ketorolac intravenously every 6 hours for patients ≤65 years of age or 15-mg ketorolac intravenously every 6 hours for patients older than 65 years of age, and 1-g acetaminophen orally every 6 hours. The control group received 0.1-mg/kg morphine intravenously every 6 hours and oxycodone combined with acetaminophen (2.5 and 325 mg), 2 tablets orally every 6 hours. Both groups started receiving pain medications immediately postoperatively and every 6 hours subsequently as requested. Patients who were part of the experimental group had the option to use intravenous morphine and/or oxycodone plus acetaminophen tablets as a rescue therapy.
Clinical variables such as sociodemographic, operative, and immediate postoperative data and pain intensity measurements were collected. Sociodemographic data included age, sex, highest educational level achieved, current smoking status, toxic habits, medical history, body mass index (BMI), and baseline serum creatinine level. Operative data included estimated blood loss, surgical time, and type of surgical anesthesia used. At the immediate postoperative time point, patient data on drug type, frequency of drug use, drug-related side effects, and hospital length of stay were collected. Lastly, pain intensity was measured using the 11-point numerical rating scale (NRS) in the preoperative holding area and at 12, 24, and 48 hours postoperatively.
Statistical Analysis
Data were expressed using frequency and percentages for categorical variables and means and standard deviations for quantitative data. In addition, comparisons between clinical variables were made using the chi-square test for categorical variables and the Student t test or analysis of variance (ANOVA) for quantitative variables. No power analysis for a sample size calculation was performed for this trial because it was considered a pilot study. A p value of 0.05 was considered significant, and differences between groups were reported with 95% confidence intervals. Statistical analysis was performed with Excel (Microsoft) and SPSS (IBM).
Source of Funding
There was no source of external funding for this study.
Results
Patient enrollment is shown in the CONSORT (Consolidated Standards of Reporting Trials) flow diagram in Figure 1. From November 2019 to March 2020, 84 patients were assessed for eligibility. Three (4%) of the 84 patients were excluded from the study because of a history of creatinine levels higher than 1.2 mg/dL (1 patient), gastrointestinal bleeding (1 patient), and a need for revision TKA equipment (1 patient) (this exclusion was established after the initial methodology to provide a reliable view of patients using solely TKA equipment). A total of 81 Hispanic patients were analyzed and fulfilled the inclusion criteria: 42 patients in the experimental group and 39 patients in the control group. No significant differences were found between the groups with regard to sociodemographic data (age, sex, highest educational level achieved, current smoking status, toxic habits, medical history, BMI, and baseline serum creatinine level). The operative data from all patients showed an overall mean surgical time of 65.1 ± 7.7 minutes and estimated blood loss of 117.5 ± 24.2 mL. Forty-four patients (54%) were classified as ASA II. All 81 of the patients underwent the surgical procedure with spinal anesthesia. The groups had similar surgical times, ASA classifications, and estimated blood loss. The sociodemographic and operative data from both groups are given in Table I.
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Fig. 1: CONSORT flow diagram for the study.
TABLE I -
Sociodemographic and Operative Data
| Variable |
Experimental Group (N = 42) |
Control Group (N = 39) |
P Value |
| Sociodemographic |
|
|
|
| Female sex*
|
31 (74%) |
35 (90%) |
0.088 |
| Age†
(yr)
|
62.5 ± 9.3 |
63.9 ± 10.1 |
0.533 |
| BMI†
(kg/m
2
)
|
34.4 ± 5.5 |
34.0 ± 4.6 |
0.698 |
| Highest educational level*
|
|
|
|
| Less than high school diploma |
8 (19%) |
5 (13%) |
0.558 |
| High school diploma |
13 (31%) |
21 (54%) |
0.051 |
| Associate degree |
8 (19%) |
2 (5%) |
0.090 |
| Bachelor degree |
13 (31%) |
10 (26%) |
0.630 |
| Graduate studies |
0 (0%) |
1 (3%) |
0.482 |
| Medical history*
|
|
|
|
| Cardiovascular problems |
32 (76%) |
29 (74%) |
1.000 |
| Endocrine problems |
16 (38%) |
21 (54%) |
0.184 |
| Rheumatologic problems |
6 (14%) |
12 (31%) |
0.108 |
| Psychiatric problems |
4 (10%) |
9 (23%) |
0.132 |
| Respiratory problems |
3 (7%) |
7 (18%) |
0.184 |
| Oncological problems |
0 (0%) |
1 (3%) |
0.482 |
| Toxic habit history*
|
|
|
|
| Alcohol overconsumption |
14 (33%) |
20 (51%) |
0.102 |
| Chronic smoking |
3 (7%) |
3 (8%) |
1.000 |
| Cannabis use |
1 (2%) |
3 (8%) |
0.347 |
| Operative |
|
|
|
| Preoperative serum creatinine†
(mg/dL)
|
0.8 ± 0.2 |
0.8 ± 0.1 |
1.000 |
| ASA class I*
|
20 (48%) |
17 (44%) |
0.824 |
| Surgical time†
(min)
|
66.6 ± 6.3 |
63.6 ± 9.0 |
0.081 |
| Estimated blood loss†
(mL)
|
117.9 ± 26.7 |
117.1 ± 23.7 |
0.894 |
*The values are given as the number of patients, with the percentage in parentheses.
†The values are given as the mean and the standard deviation.
In the experimental group, a mean of 5.9 ± 2.3 g of acetaminophen and a mean of 141.8 ± 70.8 mg of ketorolac were consumed per patient throughout the hospitalization. However, 2 patients in the experimental group also used a mean of 3.0 ± 1.4 mg of morphine as rescue opioid therapy because of uncontrolled postoperative pain. None of the patients in the experimental group requested oxycodone combined with acetaminophen as rescue therapy. In the control group, means of 28.0 ± 7.9 mg of morphine and 64.8 ± 26.0 mg of oxycodone were consumed per patient throughout the hospitalization. During the first 24 hours postoperatively, all of the patients in both groups requested analgesic drugs. However, during the 24 to 48-hour postoperative time frame, a significantly lower number of analgesic drugs were requested by the patients being treated with opioid-free drugs in the experimental group (p < 0.001) (Table II).
TABLE II -
Immediate Postoperative Frequency of Drugs Given
| Analgesic Drugs Requested Per Day |
Experimental Group* (N = 42) |
Control Group* (N = 39) |
P Value |
| 0 to 24 hours |
42 (100%) |
39 (100%) |
1.000 |
| 24 to 48 hours |
22 (52%) |
34 (87%) |
<0.001 |
*The values are given as the number of patients, with the percentage in parentheses.
The experimental group reported a significantly higher preoperative NRS pain intensity at 8.2 ± 1.8 compared with the control group at 7.1 ± 1.8 (p = 0.011). Both groups reported decreasing pain intensity from the preoperative time to the 48-hour postoperative evaluation. No significant differences were found between the groups at the 12, 24, and 48-hour postoperative evaluations (Table III).
TABLE III -
NRS
Pain Intensity Scores
| NRS Score |
Experimental Group* (N = 42) |
Control Group* (N = 39) |
P Value |
| Preoperative |
8.2 ± 1.8 |
7.1 ± 1.8 |
0.011 |
| Postoperative |
|
|
|
| 12 hours |
6.7 ± 2.9 |
5.9 ± 2.8 |
0.209 |
| 24 hours |
6.2 ± 2.0 |
6.1 ± 2.2 |
0.813 |
| 48 hours |
4.7 ± 2.1 |
4.6 ± 1.7 |
0.835 |
*The values are given as the mean and the standard deviation.
Overall, the most common drug-related side effects reported were nausea (4 patients [5%]) followed by dizziness (3 patients [4%]), vomiting (2 patients [2%]), tachycardia (1 patient [1%]), pruritus (1 patient [1%]), and headache (1 patient [1%]). None of the patients were found to have gastrointestinal bleeding or a hematoma postoperatively. The patients who were treated with the opioid-free multimodal analgesic regimen (5 [12%] of 42) showed fewer postoperative adverse drug-related side effects when compared with those treated with the traditional opioid regimen (7 [18%] of 39) (p = 0.538) (Table IV). Finally, no significant differences (p = 0.527) in the hospital length of stay were found between the patients in the experimental group (2.1 ± 0.4 days) and the control group (2.2 ± 0.5 days).
TABLE IV -
Immediate Postoperative Adverse Drug-Related Side Effects
| Side Effect |
Experimental Group* (N = 42) |
Control Group* (N = 39) |
P Value |
| Nausea |
2 (5%) |
2 (5%) |
1.000 |
| Dizziness |
1 (2%) |
2 (5%) |
0.606 |
| Vomit |
1 (2%) |
1 (3%) |
1.000 |
| Tachycardia |
1 (2%) |
0 (0%) |
1.000 |
| Pruritus |
0 (0%) |
1 (3%) |
0.482 |
| Headache |
0 (0%) |
1 (3%) |
0.482 |
| Total |
5 (12%) |
7 (18%) |
0.538 |
*The values are given as the number of patients, with the percentage in parentheses.
Discussion
To our knowledge, this is the first study that evaluated the efficacy of using an opioid-sparing postoperative multimodal analgesia protocol in a Hispanic population. In our study, patients randomized to receive the opioid-sparing multimodal analgesic regimen had reported significantly worse preoperative pain intensity scores than those who received the standard opioid protocol. Nevertheless, the opioid-sparing multimodal analgesic regimen was found to be an adequate alternative, compared with the standard opioid protocol, to reduce postoperative pain intensity and opioid consumption in Hispanic patients undergoing TKA.
Throughout the last decades, TKA has been shown to be a successful surgical procedure that provides substantial improvement in pain, functional status, and overall health-related quality of life for patient with end-stage knee osteoarthritis1,2,13. In 2007, Kurtz et al. presented a 25-year projected growth of 673% in primary TKA demand by 2030 in the United States18. Despite the increased demand for this procedure, postoperative pain control following TKA remains a well-known clinical challenge. Previous studies have shown that inadequate postoperative pain management is an important predictor of poor patient satisfaction, prolonged hospitalization, and increased risk of postoperative complications2,6.
Opioids have long been effectively used for perioperative pain management in patients undergoing primary TKA19. Despite their effectiveness, opioids can produce adverse side effects such as itching, nausea, somnolence, respiratory depression, urine retention, constipation, and addiction19. Currently, opioids have become a public health epidemic20. In 2019, >70% of 70,630 drug overdose-related deaths in the United States were associated with opioid use21. Furthermore, opioid overdose has surpassed motor vehicle accidents as the leading cause of accidental death in the United States21.
Nowadays, alternative pain management protocols such as multimodal analgesia are increasingly used in an attempt to control pain with less reliance on opioids2,19. The aim of multimodal analgesia is to maximize analgesic efficacy through the combination of several pain control regimens, while minimizing undesired opioid-related adverse side effects19. Previous studies have shown ample evidence to suggest that NSAIDs and acetaminophen are effective alternatives for decreasing opioid consumption2,19.
Both NSAIDs and acetaminophen had demonstrated analgesic and antipyretic properties through inhibitory effects on the cyclooxygenase (COX) pathway2,19. NSAIDs have peripheral tissue activity through COX-1 and COX-2 inhibition that produces an antipyretic, analgesic, and anti-inflammatory effect by limiting peripheral prostaglandin production2,22. In 2014, Lamplot et al. performed a randomized controlled trial evaluating the ability of a multimodal analgesic regimen including intravenous ketorolac (i.e., a nonselective NSAID) to provide adequate postoperative pain management. Their study demonstrated that 15 mg of intravenous ketorolac could be used as part of multimodal analgesia in patients undergoing TKA22. Similarly, Moucha et al. recommended a dose of 15 to 30 mg of intravenous ketorolac every 6 hours as a potential non-opioid alternative for a multimodal analgesia protocol23. The mechanism of acetaminophen is not yet fully understood, but it is believed to act as a central analgesic agent through several pathways, including COX-2 inhibition. Despite its limited assessment, acetaminophen has been considered an initial step in multimodal pain control24. Multiple review articles evaluating pain control in TKA have recommended up to 1 g of acetaminophen every 6 hours as an opioid alternative for a multimodal analgesic approach2,23,24. However, to our knowledge, the efficacy of NSAIDs and acetaminophen in an opioid-sparing multimodal analgesia protocol has not been assessed before in a Hispanic population.
In a retrospective study in 2021, Venugopal et al. showed that, despite the improving trends in procedure utilization, comorbidities, and length of stay among Hispanic patients undergoing primary elective TKA, there had been no improvement in postoperative adverse events14. These findings represent an alarming scenario because of the projected increase in the demand for primary TKA in the coming years18. Therefore, it is critical to focus research and health optimization efforts on improving postoperative care, especially in minority groups (e.g., Hispanic individuals) who are at an increased risk for having suboptimal outcomes such as increased postoperative pain, higher risk of postoperative infections, and lower levels of satisfaction13–17. In this study, we successfully demonstrated the use of an opioid-sparing multimodal analgesic regimen in Hispanic patients undergoing TKA, adding to the scarce literature with regard to postoperative pain management in this population, which we propose to be an effective non-opioid alternative for pain control to decrease opioid consumption.
This study had some limitations that should be considered when interpreting our findings. First, we could not be certain that the differences that we observed between our opioid-sparing multimodal analgesic regimen and the standard opioid-based protocol could not be explained by unobserved confounding factors. Second, due to the strict inclusion criteria, our results may not be generalizable outside of the Hispanic population. Third, because this was a pilot study, a larger sample with a prolonged follow-up time should be assessed in further studies. Fourth, the registration of our project in our institution (University of Puerto Rico Medical Sciences institutional review board) was established in a prospective manner, but its enrollment in a clinical trial database was not performed in a prospective manner because of our lack of knowledge at the time of the initial registration. Fifth, the exclusion of the patient who needed a TKA revision system was established after the initial methodology was determined. Lastly, opioid requirements after discharge were not assessed.
In conclusion, this pilot study demonstrated that the use of intravenous ketorolac and oral acetaminophen was an adequate multimodal analgesic regimen to reduce postoperative pain and opioid consumption in Hispanic patients undergoing TKA. Future clinical trials should monitor pain intensity and analgesic requirements at outpatient follow-up visits to gain insight into its long-term impact on pain management in the Hispanic population.
Data Sharing
A data-sharing statement is provided with the online version of the article (https://links.lww.com/JBJSOA/A479).
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