Opioid Use in Knee Arthroplasty After Receiving Intravenous Acetaminophen

Opioid Use in Knee Arthroplasty After Receiving Intravenous Acetaminophen Jennifer S. Kelly, 1 * Yekaterina Opsha, 1,2 Jennifer Costello, 1 Daryl Schiller, 3 and Eric T. Hola 1 1 Saint Barnabas Medical Center, Livingston, New Jersey; 2 Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; 3 Nyack Hospital, Nyack, New York BACKGROUND Intravenous (IV) acetaminophen may be an effective component of multimodal postoperative pain management. The primary objective of this study was to evaluate the impact of IV acetaminophen on total opioid use in postoperative patients. The secondary objective was to evaluate the effect of IV acetaminophen on hospital length of stay. METHODS This retrospective, case control study evaluated the impact of IV acetaminophen on total opioid use in surgical patients. Patients were included if they received at least one perioperative dose of IV acetaminophen and underwent a surgical knee procedure. Controls were matched and randomly selected based on procedure type, age, and severity of illness. Postoperative opioids were converted into oral morphine equivalents, and overall use was compared between groups. RESULTS One hundred patients were enrolled, with 25 patients receiving IV acetaminophen and 75 matched controls. A total of 135 mg versus 112.5 mg oral morphine equivalents were used in the IV acetaminophen group and control group, respectively (p=0.987). There were 45 mg/day oral morphine equivalents used in the IV acetaminophen group versus 37.5 mg in the control group (p=0.845). The median hospital length of stay in both groups was 3 days (p=0.799). CONCLUSION IV acetaminophen did not significantly decrease postoperative opioid use in patients who underwent surgical knee procedures. In addition, there was a nonsignificant trend toward increased opioid use in the IV acetaminophen group. There was no significant difference in hospital length of stay between the IV acetaminophen group and the control group. These findings require further study in larger patient populations and in other orthopedic procedures that typically require longer hospital stays. KEY WORDS IV acetaminophen, total opioid use, pain control, surgical patients, analgesia. (Pharmacotherapy 2014;34(12 Pt 2):22S 26S) doi: 10.1002/phar.1518 Effective pain management is an important component of postoperative care. 1 Opioids are well established as the primary treatment for postoperative pain. 2 Multimodal analgesia, which has been more widely used in recent years for This work is attributed to the Pharmacy Department at Saint Barnabas Medical Center, Livingston, NJ. No financial assistance was used in the preparation of this manuscript. This work was presented at the Eastern States Pharmacy Residency Conference, Hershey, PA, May 15, 2013. *Address for correspondence: Jennifer S. Kelly, Saint Barnabas Medical Center, 94 Old Short Hills Road, Livingston, NJ 07037; e-mail: jkelly@nets-us.com. Ó 2014 Pharmacotherapy Publications, Inc. postoperative pain, may reduce opioid use. Acetaminophen has been effectively used in combination with opioids for its analgesic effects. 2 There is evidence to suggest an opioidsparing effect with intravenous (IV) acetaminophen. Multimodal analgesia consists of both opioid and nonopioid medications, such as acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs). The objectives of a multimodal approach are to improve analgesia, reduce the amount of opioids used, and decrease opioidrelated adverse effects. 1, 2 Opioid use has been associated with dose-related adverse effects that may delay recovery. The adverse effect profile of

IV ACETAMINOPHEN IN KNEE ARTHROPLASTY Kelly et al 23S opioids includes nausea, vomiting, sedation, respiratory depression, dizziness, drowsiness, constipation, and decreased gastrointestinal motility, which can also lead to the development of postoperative ileus. Therefore, the concept of opioid-sparing analgesics to improve postoperative outcome and decrease hospital length of stay is appealing. 3 In November 2010, the United States Food and Drug Administration approved a new IV formulation of acetaminophen (Ofirmev, Cadence Pharmaceuticals, San Diego, CA) for the management of mild to moderate pain, moderate to severe pain with adjunctive opioid analgesics, and reduction of fever in adults and children 2 years of age and older. 3, 4 Until that time, acetaminophen was available only in oral and rectal formulations in the United States. Acetaminophen is a centrally acting analgesic and antipyretic. The pharmacokinetics are favorable for acute pain relief, with peak analgesia occurring within 15 minutes (T max = 5 15 min), compared to 10 to 60 minutes with oral formulations and a variable time to peak effect with rectal formulations. 2, 3 Currently available data about the overall clinical benefit of IV acetaminophen are inconclusive. One study 1 concluded that IV acetaminophen significantly reduced morphine consumption in the 24-hour postoperative period following hip and knee arthroplasty. However, another study 5 found that IV acetaminophen resulted in a non statistically significant reduction in opioid consumption compared with placebo for postoperative pain associated with hip arthroplasty. The primary objective of this study was to evaluate the opioid-sparing effect of IV acetaminophen in postoperative patients. Materials and Methods Study Design This single-center, retrospective, case control study evaluated the effect of IV acetaminophen on total opioid use in postoperative patients undergoing knee arthroplasty. The secondary objective was to determine the effect of IV acetaminophen on hospital length of stay. Patients and randomly selected controls were matched in a 1:3 ratio based on procedure type, All Patient Refined- Diagnosis Related Groups (APR-DRG) severity of illness score, and age. All patients were postsurgical after a knee procedure and received at least one perioperative dose of IV acetaminophen. Controls underwent similar surgical knee procedures but did not receive any IV acetaminophen. Population Patients were identified through an internal billing database based on International Classification of Diseases, Ninth Revision (ICD-9) procedure code. Procedures included in this analysis were total knee replacement (81.54), total knee revisions (81.55), modifiers to specific knee compartments (0.80 0.84), below-knee amputation (84.15), and amputation through the foot. (84.12). Patients 18 years of age and older who underwent a surgical knee procedure between January 2012 and March 2013 in a tertiary 600-bed teaching hospital were included. Other types of surgical procedures were reason for exclusion. Pain scores were measured by a visual analog scale (VAS), ranging from no pain at all (score of 0) to the worst pain possible (score of 10). The protocol for this study was approved by the institutional review board. Medications Intravenous acetaminophen is available as a 10 mg/ml (100 ml) solution packaged in a glass vial. The recommended dose in adults weighing more than 50 kg is 1000 mg every 6 hours or 650 mg every 4 hours. 3 Each dose of IV acetaminophen was administered as a 15-minute IV infusion. Patients received IV acetaminophen either in the operating room or at any time during the perioperative period. Statistical Analysis The amount of opioids used was converted into oral morphine equivalents using a prespecified conversion factor in which 7.5 mg hydromorphone and 20 mg oxycodone are equivalent to 30 mg morphine. 6 Intravenous fentanyl was excluded from the analysis because it was administered in the operating room to both groups of patients. Through assessment for a normal distribution, more than 90% of the data fell within 1 standard deviation. Therefore, a nonparametric statistical test, the Mann Whitney U test, was used for analysis. The median was used as the descriptive statistic. A p-value of less than or equal to 0.05 indicated statistical significance. All statistical analyses were conducted using SPSS software, version 19 (IBM Corp., Armonk, NY).

24S Supplement to PHARMACOTHERAPY Volume 34, Number 12, 2014 Results Demographics The study population consisted of 100 patients (25 cases and 75 controls). The two groups were similar in age, body mass index (BMI), and indication for knee procedure (Table 1). The average age was 63.9 years in the IV acetaminophen group and 65.3 years in the control group. Based on calculated BMI, more than half of the patients were overweight or obese. There were nine (36%) patients classified as overweight and 13 (52%) classified as obese in the IV acetaminophen group, compared with 22 (29%) and 47 (63%), respectively, in the control group. The most common indication for receiving the surgical knee procedure in both groups was osteoarthritis. Although the distribution of baseline pain scores in the low to moderate range was similar between both groups (84% in the IV acetaminophen group versus 88% in the control group), more patients in the IV acetaminophen group reported high pain scores (16% in the IV acetaminophen group compared with 12% in the control group). Table 1. Baseline Characteristics IV Acetaminophen cases (n=25) No IV Acetaminophen Controls (n=75) Sex (%) Male 9 (36) 37 (49) Female 16 (64) 38 (51) Age (yrs) Average age SD 63.9 12.7 65.3 10.7 BMI (%) 18.5 24.9 (normal) 3 (12) 6 (8) 25.0 29.9 9 (36) 22 (29) (overweight) 30.0 (obese) 13 (52) 47 (63) Indication for procedure (%) Osteoarthritis 20 (80) 59 (79) Loosening or 2 (8) 7 (9) complication of Prosthetic joint Diabetes with 2 (8) 8 (11) peripheral circulatory disorder/ infection Closed fracture or 1 (4) 1 (1) trauma Baseline pain scores (%) Low (0 3) 11 (44) 46 (61) Moderate (4 6) 10 (40) 20 (27) High (7 10) 4 (16) 9 (12) SD = standard deviation; BMI = body mass index in kg/m 2. Postoperative Opioid Use There was no statistical significance observed in total postoperative opioid use between the IV acetaminophen group and the control group (Figure 1). A total of 135 mg oral morphine equivalents were administered in the IV acetaminophen group versus 112.5 mg oral morphine equivalents in the control group (p=0.987). There was also no significant difference in the amount of daily oral morphine equivalents between the two groups (Figure 2). Forty-five milligrams of daily oral morphine equivalents was used in the IV acetaminophen group versus 37.5 mg in the control group (p=0.845). Case patients received a mean of three IV acetaminophen doses, with a range of one to eight doses. The most common dosing regimens were 1000 mg IV once, 1000 mg IV every 6 hours, and 1000 mg IV every 8 hours. Ten of the 25 case patients (40%) received only one dose of IV acetaminophen. Length of Stay The median length of stay for both the IV acetaminophen group and the control group was 3 days (p=0.799). The length of stay ranged from 2 to 43 days in the IV acetaminophen group versus 2 to 81 days in the control group (Table 2). Figure 1. Cumulative postoperative opioid use during admission. Figure 2. Corrected daily morphine equivalents.

IV ACETAMINOPHEN IN KNEE ARTHROPLASTY Kelly et al 25S Table 2. Hospital Length of Stay Median LOS (days) LOS Range (days) IV acetaminophen (cases) 3 2 43 No IV acetaminophen 3 2 81 (controls) p=0.799 LOS = length of stay. Discussion Patients receiving multimodal analgesia often have lower pain intensity scores, lower postoperative opioid consumption, and fewer opioidrelated adverse effects, such as sedation, respiratory depression, and constipation. 1, 2 Therefore, opioid-sparing strategies may have beneficial outcomes for patients. This retrospective, case control study demonstrated that IV acetaminophen did not significantly decrease daily or total postoperative opioid use in patients who underwent surgical knee procedures. In addition, there was a nonsignificant trend toward increased opioid use in the IV acetaminophen group. The types of surgical knee procedures analyzed included total knee replacement, revision of the knee replacement, below-knee amputation, and amputation through the foot. Pain control is one of the most important indicators for overall patient satisfaction. 7 However, predicting postoperative pain after a knee procedure can be difficult. 8 There is growing evidence that postoperative pain may be higher in patients who were previously diagnosed with osteoarthritis. 9 In our study, osteoarthritis was the most common indication for patients receiving the surgical knee procedure. The majority of the baseline pain intensity scores were in the low (0 3) to moderate (4 6) range in both groups. More patients in the control group reported pain scores of 0 to 3, while there was a more even distribution of pain scores of 0 to 3 and 4 to 6 in the IV acetaminophen group. Major orthopedic surgery can be extremely painful, and monotherapy with acetaminophen may not provide complete pain relief. There are many factors that can contribute to pain scores. Surgical technique can influence postoperative pain. Patients undergoing total knee replacement with a parapatellar approach have reported higher pain scores than patients undergoing the same procedure with a subvastus approach. 10 There are also age-related differences in pain, opioid use, and opioidrelated adverse effects in patients 60 years of age or older. Older adults have been shown to be more sensitive to opioid side effects, with no difference in pain control. 11 The results of this study are in contrast to some of the studies previously mentioned that cite a significant reduction in the amount of postoperative opioids used. A study concluded that 1000 mg of IV acetaminophen every 6 hours for 24 hours significantly reduced morphine consumption in patients undergoing hip and knee arthroplasty procedures. The average age of these patients was 61.7 years, with most patients (90.7%) receiving four doses of IV acetaminophen over 24 hours. 1 In contrast, another study 5 showed a non statistically significant reduction in opioid use compared with placebo in patients undergoing hip arthroplasty. With the exception of IV acetaminophen having a faster onset of action than oral or rectal formulations, the half-lives of all three formulations are similar, and the duration of effect for all three formulations is 4 to 6 hours. 2 After the administration of 1000 mg of IV, oral, or rectal acetaminophen, the mean plasma peak concentration (C max ) values are 21.6, 12.3, and 6.1 lg/ ml, respectively. 12 Intravenous acetaminophen achieved higher plasma cerebrospinal fluid (CSF) levels compared with oral or rectal formulations. The CSF bioavailability over 6 hours (AUC 0 6 ) was 24.9 lg/hr/ml after receiving 1000 mg IV acetaminophen, 14.2 lg/hr/ml after receiving 1000 mg oral acetaminophen, and 10.3 lg/hr/ml after receiving 1300 mg rectal acetaminophen. 12 The peak plasma concentrations and elimination half-lives are similar for the various oral formulations, with a systemic bioavailability of ~80%. 13 In addition, the cost of IV acetaminophen is $43.68/day, which is higher than that of the oral or rectal formulations, at $0.12/day and $5.64/day, respectively. 2 The costs of IV tubing and administration should also be considered. Intravenous acetaminophen may be a suitable option for patients who cannot receive oral or rectal medications and for those who cannot take or tolerate other IV analgesics or antipyretics. However, given the inconsistent clinical data that are currently available, the similar pharmacokinetics, and the large difference in price between the formulations, IV acetaminophen may not be a cost-effective option for most patients. This study showed no significant difference in hospital length of stay between the IV acetaminophen group and the control group. Although

26S Supplement to PHARMACOTHERAPY Volume 34, Number 12, 2014 both groups had a median length of stay of 3 days, the average length of stay was 5.72 days in the IV acetaminophen group and 9.16 days in patients who did not receive IV acetaminophen. There was no statistical significance between these two groups. Both groups had a number of outliers, with the length of stay ranging from 2 to 43 days in the IV acetaminophen group, compared with 2 to 81 days in the control group. Reducing hospital stay leads to a reduction of hospital expenses. One study 14 showed that reducing length of stay from 9 to 3.7 days for patients undergoing total knee arthroplasty helped cut hospital expenses by 42%. However, this decrease in hospital stay has also been associated with an increase in hospital readmission rates and an increase in readmission for wound infections. 15, 16 The initiation of payment bundling by the Centers for Medicare and Medicaid Services has the potential to reduce costs without compromising patient outcomes. It produces a strong incentive for the recipient of the bundled payments to not discharge patients too early. 17 There are several limitations to this study. The study was a retrospective, single-center evaluation of 100 patients. Future evaluation is warranted in a larger patient population in a prospective, randomized, multicenter design. Although this study focused on evaluating the effects of IV acetaminophen in patients undergoing surgical knee procedures, the use of IV acetaminophen for postoperative pain control has also been evaluated in patients undergoing abdominal, 18 dental, 19 and cardiac procedures. 20 Another limitation to this study included not analyzing previous patient-specific opioid exposure, which included opioids prior to the surgical procedure and as well as history of chronic opioid use. This is particularly relevant because prior opioid users may recognize the pharmacologic effects of opioids, suggesting the presence of a nocebo effect on subjective pain scores. In conclusion, our study did not show a decrease in daily or total postoperative opioid use in patients who underwent surgical knee procedures and received IV acetaminophen. It also did not show a significant reduction on overall hospital length of stay. References 1. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology 2005;102:822 831. 2. Yeh YC, Reddy P. Clinical and economic evidence for intravenous acetaminophen. Pharmacotherapy 2012;32:559 579. 3. Joshi GP. Multimodal analgesia techniques and postoperative rehabilitation. Anesthesiol Clin N Am 2005;23:185 202. 4. Cadence Pharmaceuticals, Inc. Ofirmev (acetaminophen) package insert. San Diego, CA; 2010. 5. Gimbel JS, Leclerc A, Royal MA, Smith H, Breitmeyer J. Efficacy and safety of IV acetaminophen in the treatment of pain following total hip arthroplasty: results of a double-blind, randomized, placebo-controlled, multiple-dose, 24 hour study. Am Acad Pain Med 2008. 6. Opioid Conversion Table. LexiComp Web site. Available from http://online.lexi.com. Accessed May 8, 2013. 7. Hamilton DF, Lane JV, Gaston P, et al. What determines patient satisfaction with surgery? A prospective cohort study of 4709 patients following total joint replacement. BMJ Open 2013;3:e002525. 8. Lunn TH, Gaarn-Larsen L, Kehlet H. Prediction of postoperative pain by preoperative pain response to heat stimulation in total knee arthroplasty. Pain 2013;13:313 318. 9. Polkowski GG II, Ruh EL, Barrack TN, Nunley RM, Barrack RL. Is pain and dissatisfaction after TKS related to early-grade preoperative osteoarthritis? Clin Orthop Relat Res 2013;471:162 168. 10. Curtin B, Yakkanti M, Malkani A. Postoperative pain and contracture following total knee arthroplasty comparing parapatellar and subvastus approaches. J Arthroplasty 2014;29:33 36. 11. Petre BM, Roxbury CR, McCallum JR, Defontes KW III, Belkoff SM, Mears SC. Pain reporting, opiate dosing, and the adverse effects of opiates after hip or knee replacement in patients 60 years old or older. Geriatr Orthop Surg Rehabil 2012;3:3 7. 12. Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract 2012;12:523 532. 13. Ameer B, Divoll M, Abernethy DR, Greenblatt DJ, Shargel L. Absolute and relative bioavailability of oral acetaminophen preparations. J Pharm Sci 1983;72:955 958. 14. Healy WL, Rana AJ. Hospital economics of primary total knee arthroplasty at a teaching hospital. Clin Orthop Relat Res 2011;469:87 94. 15. Cram P, Lu X, Kates SL, Singh JA, Li Y, Wolf BR. Total knee arthroplasty volume, utilization, and outcomes among medicare beneficiaries, 1991 2010. JAMA 2012;308:1227 1236. 16. Bozic KJ, Lorrayne W, Vail TP, Maze M. Bundled payments in total joint arthroplasty: targeting opportunities for quality improvement and cost reduction. Clin Orthop Relat Res 2014;472(1):188 193. doi:10.1007/s11999-013-3034-3. 17. Sood N, Huckfeldt PJ, Escarce JJ, Grabowski DC, Newhouse JP. Medicare s bundled payment pilot for acute and postacute care: analysis and recommendations on where to begin. Health Aff 2011;30:1708 1717. 18. Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther 2010;32:2348 2369. 19. Moller PL, Juhl GI, Payen-Champenois C, Skoglund LA. Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery. Anesth Analg 2005;101:90 96. 20. Cattabriga I, Pacini D, Lamazza G, et al. Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial. Eur J Cardiothorac Surg 2007;32:527 531.