Impact of Intravenous Acetaminophen on Reducing Opioid Use After Hysterectomy

Transcription

1 Impact of Intravenous Acetaminophen on Reducing Opioid Use After Hysterectomy Brittany O. Herring,* Sheila Ader,* Angel Maldonado, Carla Hawkins, Margaretta Kearson, and Madeline Camejo Pharmacy Department, Memorial Regional Hospital, Hollywood, Florida STUDY OBJECTIVE To examine the impact of intravenous acetaminophen on the total quantity of opioids (in morphine equivalents) administered within the first 48 hours postoperatively and perioperatively, while still affording patients adequate analgesia, in women who underwent total abdominal hysterectomies. DESIGN Retrospective chart review. SETTING Tertiary care community hospital. PATIENTS One hundred women underwent total abdominal hysterectomies performed by a single surgeon: 50 patients received opioids only (fentanyl, morphine, hydromorphone, meperidine, or oxycodone), without the addition of any acetaminophen, between January 1 and March 28, 2011, and 50 patients received intravenous acetaminophen 1000 mg every 6 hours in addition to opioids (multimodal group) between May 1 and July 16, 2012 (time period coincided with the addition of intravenous acetaminophen to the hospital formulary). Patients in both groups were also given nonopioids (celecoxib, dexmedetomidine, aspirin, or tizanidine) perioperatively. MEASUREMENTS AND MAIN RESULTS Patients in both groups had a mean age of 55 years (mean SD yrs in the multimodal group, yrs in the opioids-only group), surgery time of ~2 hours ( min in the multimodal group, min in the opioids-only group), and an anesthesia time of ~3.5 hours ( min in the multimodal group, min in the opioids-only group). During postoperative days 1 2, intravenous acetaminophen reduced opioid use by 31% (mean SD mg in the multimodal group vs mg in the opioids-only group, p=0.003) and by 26% during the total perioperative period, defined as preoperative, intraoperative, recovery room, and postoperative days 1 2 (73 24 mg in the multimodal group vs mg in the opioids-only group, p=0.001). CONCLUSION The multimodal approach to perioperative analgesic management, which includes concurrent administration of intravenous acetaminophen and opioids, is effective in reducing the total average amount of opioids administered on postoperative days 1 2 and perioperatively. Limitations of this study include its short duration, retrospective design, and single-site setting. These results may not be generalized to patients undergoing other types of obstetric-gynecologic surgeries. KEY WORDS acetaminophen, Ofirmev, opioids, hysterectomy, postoperative, perioperative. (Pharmacotherapy 2014;34(12 Pt 2):27S 33S) doi: /phar.1513 Meeting Presentation: Presented at the Second Annual Florida Residency Conference, University of Florida, Gainesville, Florida, May 9 10, *Address for correspondence: Brittany Herring and Sheila Ader, Pharmacy Department, Memorial Regional Hospital, 3501 Johnson St., Hollywood, FL 33021; sader@mhs.net. Ó 2014 Pharmacotherapy Publications, Inc. Opioids such as fentanyl, morphine, hydromorphone, meperidine, and oxycodone are widely used during the perioperative period (i.e., preoperatively, intraoperatively, recovery room, and postoperatively) to prevent, reduce, and manage pain in surgical patients. Opioids, however, are associated with a variety of adverse

2 28S SUPPLEMENT TO PHARMACOTHERAPY Volume 34, Number 12, 2014 effects. Their adverse effect profile includes sedation, decreased cognition, delirium, respiratory depression, gastrointestinal immotility, nausea, constipation, and pruritus. 1 This causes opioid usage to be controversial and potentially quantity limiting. Many methods minimize the adverse effects of opioids, including dose reduction, symptomatic management, opioid rotation, and changing the route of administration. 1 Since the United States Food and Drug Administration s approval of intravenous nonopioids, there has been a shift toward increasing the use of nonopioids (e.g., acetaminophen, ibuprofen, celecoxib, and dexmedetomidine) while subsequently decreasing the amount of opioids used. Intravenous nonopioids such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSA- IDs), specifically ibuprofen, have both efficacy and analgesic effects. These effects include lowering the postoperative Visual Analog Scale (VAS) score, extubation time, and opioid consumption. They also lower the amount of nausea, vomiting, and sedation. While research supports that intravenous nonopioids may provide opioid-sparing effects, it may be as effective to transition patients to oral analgesics versus using another intravenous medication. 2 6 Health care practitioners are trending toward the new standard of care, multimodal analgesia, which includes the use of opioids and nonopioids. According to the 2012 Anesthesiologist Guidelines on Pain Management, perioperative pain management includes the use of epidural or intrathecal opioids, systemic opioid patient-controlled analgesia (PCA), and local anesthetics. Postoperative adjunctive pain management should include the usage of around-the-clock nonopioid analgesics such as NSAIDs and acetaminophen. (There is not a specific recommendation for pain management in abdominal procedures.) 7 Abdominal hysterectomies rank highly among gynecologic procedures for the development of pain. 8 For treatment of postoperative pain after this procedure, the multimodal analgesia approach is effective, with NSAIDs usually being used for the management of mild to moderate postoperative pain and as adjuncts with other analgesics in moderate to severe postoperative pain. 8 In the World Health Organization s multimodal pain management stepladder, nonopioid analgesics like acetaminophen are recommended to be used for mild pain as single agents and adjunctively in moderate to severe pain. 9 The potential disadvantages with using acetaminophen are hepatic including significant liver dysfunction (especially in large doses) and acetaminophen s effects on those taking substances that induce hepatic enzymes. 10 Acetaminophen is a centrally acting analgesic whose exact mechanism in reducing pain is unknown but may be due to an inhibition of central prostaglandin synthesis (cyclooxygenase-2) and an elevation of the pain threshold. Intravenous acetaminophen s pharmacokinetic effects are dose proportional at 500, 650, and 1000 mg. 10 After administration of a 15-minute intravenous infusion of acetaminophen, the maximum concentration (C max ) is up to 70% higher, whereas overall exposure between the oral and intravenous forms are similar. 10 The drug is widely distributed throughout body tissues. Acetaminophen is primarily metabolized in the liver by three separate pathways, including the cytochrome P450 enzyme pathway. 10 Its metabolite, N-acetyl-p-benzoquinone imine, is mainly excreted in the urine within 24 hours. For treatment of pain (mild to moderate and moderate to severe pain) along with adjunctive opioid analgesics in patients weighing 50 kg or greater, the dosage of intravenous acetaminophen is 650 mg every 4 hours or 1000 mg every 6 hours, with a maximum of 4 g/day. 9 For patients with severe renal impairment (creatinine clearance 30 ml/min), longer dosing intervals and a reduced total daily dose of acetaminophen are warranted. 9 Acetaminophen is also contraindicated in patients with severe hepatic impairment or severe active liver disease. 10 The opioid-sparing effects of intravenous acetaminophen have been documented in a substantial amount of research. From our review of the literature, however, we did not find any clinical trials on the postoperative use of intravenous acetaminophen in patients undergoing total abdominal hysterectomies. Advantageously, trials in patients undergoing other surgical procedures showed that intravenous acetaminophen met safety and efficacy pain endpoints, provided opioid-sparing, and caused inconsistent reductions in opioid-related adverse effects (e.g., sedation, confusion, and respiratory depression). Intravenous acetaminophen increased analgesia, analgesic effects on mobility, time to analgesic rescuing (the time until additional analgesia is needed), recovery quality, and patient satisfaction. Intravenous acetaminophen also reduced the time to extubation, the need for analgesic 2, 4 6 rescuing, and the duration of hospital stay. A study 11 compared both dosages of intravenous acetaminophen (1000 mg every 6 hr and

3 INTRAVENOUS ACETAMINOPHEN Herring et al 29S 650 mg every 4 hr) after patients underwent abdominal laparoscopic surgery. Prior to randomization, the investigator selected the opioid for PCA rescue. Nonopioids, including products containing acetaminophen, NSAIDs, and aspirin, were not allowed. Opioids were restricted once the first dose of acetaminophen was administered in both groups. Compared with the placebo, intravenous acetaminophen showed a statistically significant efficacy with regard to pain. This means that a significantly reduced sum of pain intensity was noted in both dosing groups. There was a significantly shorter time to meaningful pain relief in the 1000 mg dosing group, but not a significant difference between dosing groups for analgesic rescue during the first 12 hours. Weaknesses of the study include that the duration was only 24 hours and it excluded many elderly patients (> 80 yrs old). It also excluded those taking one of nine herbal products (chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, St. John s wort, or valerian), those taking monoamine oxidase inhibitors (MAOIs) within 7 days of surgery, and those with a body mass index not within the kg/m 2 range. Some of the other weaknesses include that the study evaluated only minimal to moderate pain and not patients with severe pain (VAS scores 70 mm on a 100-mm scale labeled with no pain at its left terminus and worst pain imaginable at its right terminus). 11 The purpose of this study was to examine the impact of intravenous acetaminophen on the total quantity of opioids (in morphine equivalents) administered within the first 48 hours postoperatively and perioperatively in women who underwent total abdominal hysterectomies in a community hospital setting. To our knowledge, this is the first report evaluating the use of intravenous acetaminophen and opioid-sparing in this patient population. Methods This was a retrospective, observational, singlesite study conducted in a large, tertiary care community hospital setting. The hospital s institutional review board approved the study. Patients were stratified into two groups: the opioids-only group and the multimodal group. Patients in the opioids-only group received opioids (fentanyl, morphine, hydromorphone, meperidine, or oxycodone), without the addition of any intravenous acetaminophen, between January 1 and March 28, Patients in the multimodal group received around-the-clock intravenous acetaminophen in addition to opioids between May 1 and July 16, 2012 (time period coincided with the addition of intravenous acetaminophen to the hospital formulary). Patients in both groups were also given nonopioids (celecoxib, dexmedetomidine, aspirin, or tizanidine) perioperatively. Patients were identified through a detailed screening process that included an internal computer database system, which used hospital coding of specific criteria (i.e., patients undergoing total abdominal hysterectomy performed by a single surgeon during predefined time periods). Data was collected using internal patient databases and recordkeeping sources: EpicCare and Willow Inpatient Pharmacy System (Epic Systems Corp., Verona WI), CGI Sovera HIM (Health Information Management) system (CGI Group Inc., Montreal, QC, Canada), and IDX CareCast (IDX Systems Corp., South Burlington, VT). Patients who underwent total abdominal hysterectomy procedures at a community hospital were eligible for inclusion in this study. Other inclusion criteria were that all patients had to be women ( 18 yrs old) who were seen by a single surgeon and received at least 1 g of intravenous acetaminophen postoperatively. Patients were excluded if they were chronic opioid users, defined as patients receiving scheduled opioids prior to surgery, either at home or as an inpatient. Patients were also excluded if they received as needed doses of acetaminophen via any route or if they weighed less than 50 kg. (Intravenous acetaminophen is dosed based on body weight in low-weight patients.) In the multimodal group, intravenous acetaminophen was infused over 15 minutes intraoperatively, in the recovery room, and/or postoperatively; patients were administered 1000 mg intravenously every 6 hours. Perioperative opioids included in this study were morphine, fentanyl, hydromorphone, oxycodone, and meperidine. (Perioperative is defined as preoperative, intraoperative, recovery room and postoperative days 1 2.) We measured total opioid use by calculating the average amount of opioids (in mg), then converting to morphine equivalents. Opioid conversions to rounded morphine equivalents are shown in Table All data are expressed as descriptive statistics. Comparisons of baseline characteristics

4 30S SUPPLEMENT TO PHARMACOTHERAPY Volume 34, Number 12, 2014 Table 1. Opioid Conversions to Intravenous Morphine Equivalents 12 Opioid Opioid Quantity (mg) Equivalent Intravenous Morphine Dose (mg) i.v. fentanyl i.v. morphine i.v. hydromorphone i.v. meperidine 10 1 p.o. hydromorphone p.o. oxycodone 10 5 p.o. morphine 10 3 (i.e., age, nonopioid use, surgical time, and anesthesia time) between the opioids-only and the multimodal groups were analyzed using the v 2 test. The amount (in mg) of opioids per drug for each patient was collected for the preoperative, intraoperative, recovery room, and postoperative days 1 2 periods. All data were placed into a spreadsheet; then the opioid doses were calculated and converted into their total amounts in morphine equivalents. The parametric data from both groups, in addition to the patients age, were analyzed by using a 2-sample Student t test with the NCCS 2007 statistical software program (NCSS; LLC, Kaysville, UT). A value of p 0.05 indicated a statistically significant difference. Statistical analysis was performed on these data by comparing means with standard deviations. Results All patients who underwent a hysterectomy were screened until accrual of a total of 100 patients (50 in each group) (Figure 1). Patients in both groups had a mean age of 55 years (mean SD yrs in the multimodal group, yrs in the opioids-only group); a mean surgery time of ~2 hours ( min in the multimodal group, min in the opioids-only group); and a mean anesthesia surgery time of ~3.5 hours ( min in the multimodal group, min opioids-only group) (Table 2). Use of intravenous acetaminophen resulted in a clinically and statistically significant 31% reduction in average postoperative days 1 2 opioid use in the multimodal group (mean SD mg in the multimodal group vs mg in the opioids-only group, p=0.003) (Table 3, Figure 2). In the recovery room, however, there was not a statistically sig- Opioids Only 82 pa ents screened 50 pa ents selected 158 pa ents screened Multimodal (Opioids and IV Acetaminophen) 76 pa ents screened 50 pa ents selected Figure 1. Schematic of the patient selection process. All surgical patients undergoing total abdominal hysterectomies were screened until a total of 100 patients (50 patients in the opioids-only group and 50 patients in the multimodal group) were included. Table 2. Baseline Characteristics of the Study Patients Characteristic Multimodal Group (n=50) Group (n=50) p Value Age (yrs) Surgery time (min) Anesthesia time (min) Data is mean SD values. Table 3. Perioperative Opioid Use in Morphine Equivalents Perioperative Period Preoperative period Intraoperative period Multimodal Group (mg) Group (mg) p Value 15 5(n=36) 15 7(n=38) (n=42) 14 6(n=39) a Recovery room 4 5(n=48) 4 5(n=46) Postoperative (n=39) (n=44) a days 1 2 Total perioperative period (n=36) (n=42) a Total perioperative period is defined as preoperative, intraoperative, recovery room, and postoperative days 1 2. Data is mean SD values. a Statistically significant. Table 4. Perioperative Nonopioid Analgesic Use Nonopioid Analgesic Multimodal Group (n=50) Group (n=50) p Value Celecoxib 41 (82) 48 (96) a Dexmedetomidine 21 (42) 2 (4) Aspirin 3 (6) 2 (4) NS Tizanadine 1 (2) 0 (0) NS NS = not significant. Data is no. (%) of patients. a Statistically significant.

5 INTRAVENOUS ACETAMINOPHEN Herring et al 31S Mul modal Figure 2. Postoperative patients opioid use in the opioidsonly group (n=50) and the multimodal group (n=50) who underwent total abdominal hysterectomies. The differences between opioid use on postoperative days 1 2 and total perioperative use (i.e., perioperatively, intraoperatively, recovery rooms and postoperatively) where significant between the groups (p=0.003 and p=0.001, respectively). nificant difference in opioid use between the two groups (4 mg vs 4 mg, p=0.446) (Table 3). Intravenous acetaminophen usage also resulted in a statistically significant 26% reduction in the average amount of opioids used during the total perioperative period with the multimodal approach. An average of 99 mg of morphine equivalents was used in the opioidsonly group versus an average of 73 mg of morphine equivalents in the multimodal group (p=0.001) (Table 3). Preoperatively, there was not a statistically significant difference in the average amount of opioids used between the two groups (15 mg vs 15 mg, p=0.907) (Table 3). However, there was a statistically significant difference in the average amount of opioids used intraoperatively between the two groups (10 mg in the multimodal group vs 14 mg in the opioids-only group, p=0.002) (Table 3). Discussion Literature shows that intravenous acetaminophen meets safety and efficacy pain reduction end points while also providing an opioid-sparing effect. To our knowledge, this is the 2, 4 6 first report evaluating opioid-sparing effects of intravenous acetaminophen in patients undergoing total abdominal hysterectomies. The data collected in this study showed that there were statistically significant differences between the multimodal and opioids-only groups in the amounts of opioids used intraoperatively and postoperatively on days 1 2, as well as during the total perioperative period. Compared with the opioids-only group, opioid use was significantly reduced in the multimodal group: 31% postoperatively on days 1 2 and 26% during the total perioperative period. On the other hand, some studies do not support the use of intravenous acetaminophen, such as in a study 3 where there was only a 5-mg difference in opioid use between the oral and intravenous acetaminophen groups. Likewise, in another study, 13 intravenous acetaminophen was only considered comparable to ibuprofen in providing opioid-sparing effects, but in a third study, intravenous acetaminophen reduced meperidine use. 2 When selecting among nonopioids intravenous NSAIDs and acetaminophen for the multimodal approach, it is important to consider whether the agents are comparable to one another regarding efficacy and safety. In a study, 13 the intravenous acetaminophen dose was considered comparable to the oral ibuprofen dose in providing opioid-sparing effects (reducing the amount of morphine PCA) after cesarean delivery. In this study, there was a nonstatistically significant (p=0.628) reduction in the cumulative dose of postoperative morphine, which is similar to the results of our study, with the exception of statistical significance being achieved. Additionally, high patient satisfaction with analgesia occurred in both groups. A weakness of this study was the comparison of cohorts using different routes of administration. Noticeable advantages of intravenous acetaminophen compared with NSAIDs include a reduced likelihood of gastrointestinal bleeding complications, use in specific populations such as pregnant women, and fewer cardiovascular issues. A multimodal approach that included intravenous acetaminophen to provide opioidsparing effects was shown to be efficacious in the literature, including one study. 11 This trial showed a statistically significant difference in efficacy, reduced the sum of pain intensity, and shortened the time to meaningful pain relief. Use of intravenous acetaminophen in the multimodal approach effectively provides analgesic effects, although its mechanism does not involve opioid receptors. Acetaminophen lowers prostaglandin levels, which are associated with pain, and ultimately helps prevent pain receptors from passing the pain message to 10, 11, 13, 14 the brain. In another study, 2 concurrent intravenous acetaminophen significantly lowered the pain scores (Behavioral Pain Scale and VAS) and reduced meperidine use compared with opioids alone ( mg vs mg) in

6 32S SUPPLEMENT TO PHARMACOTHERAPY Volume 34, Number 12, 2014 intensive care patients undergoing major abdominal or pelvic surgery. An overall weakness of this study was the specificity in only evaluating patients who would be ventilated and thus the most critically ill patients. Although intravenous acetaminophen increases analgesic relief and generalized opioid-sparing in addition to rescue analgesia, pain scores, and reducing the amount of opioid PCA, more research on the use of intravenous acetaminophen postoperatively and perioperatively in other patient populations is warranted. 4 Likewise, this study demonstrated a reduction in rescue analgesia and the amount of PCA used in the multimodal arm compared with the opioidsonly arm. Despite the benefits observed, this study had several limitations. The use of nonopioids (i.e., celecoxib and dexmedetomidine) in both groups was a confounding variable. Perioperative nonopioid analgesics were administered to both the opioids-only and the multimodal groups. There was a statistically significant difference between the proportions of patients in the multimodal group versus the opioids-only group who used celecoxib (82% vs 96%, p=0.002) (Table 4). The difference was not significant for those taking dexmedetomidine (42% vs 4%, p=0.090), aspirin (6% vs 4%, p=ns), or tizanadine (2% vs 0%, p=ns) (Table 4); nonetheless, any of the agents may have played a role in increasing patient analgesia postoperatively. Research indicates that dexmedetomidine may play a role not only in sedation but also in analgesia. 15 While the differences in the amount of dexmedetomidine use between the two groups were not statistically significant, a potential clinically significant difference may have been observed. This further emphasizes the role and efficacy of the multimodal approach in perioperative pain management. Patient-specific limitations also existed; only female patients undergoing total abdominal hysterectomies were included. By including only specific patient populations, this limits the ability of the study results to be applied in a generalized form to various types of patient populations in different inpatient settings. On the other hand, this also allowed for a controlled environment, with limited variability, to thoroughly assess the distinct differences between the two groups use of intravenous acetaminophen. In addition, there were both advantages and disadvantages created by only observing the patients who underwent total abdominal hysterectomies performed by a single surgeon. Advantageously, one surgeon used the same standard technique on performing the hysterectomies and selecting the medications administered. The disadvantages were that by using only one surgeon s patients, it may have limited the type of patients selected. Procedural similarities may have also limited the variability found in multiple real-world settings. There were also a few other limitations to the study. The statistical analysis limitation included that we did not perform a power calculation to determine the appropriate sample size. Ideally, in future studies, these effects can be mirrored with larger patient populations. Finally, data on safety, pain scale scores, and hospital duration were not collected in this study, which allowed for the specific focus to be on the amount of opioids used within each group. Conclusion Postoperative and perioperative use of intravenous acetaminophen as an adjunct analgesic in patients undergoing total abdominal hysterectomy procedures was effective in providing opioid-sparing effects. Intravenous acetaminophen potentially reduced the frequency of respiratory depression, gastrointestinal immotility, cognitive impairment, and sedation commonly observed with opioids. Additional research should be conducted to further explore this potential advantage in other types of surgeries as well as to investigate intravenous acetaminophen s role as a sole agent in providing opioid-sparing effects. Overall, it can be concluded that the multimodal approach, which included intravenous acetaminophen combined with other nonopioids, is effective in reducing the average amount of opioids used postoperatively and perioperatively. Acknowledgments We would like to acknowledge Drs. Simon Leung, Chad Edgar, and Joseph Loskove for their support in preparation for this research project. References 1. Swegle JM, Logemann C. Management of common opioidinduced adverse effect. Am Fam Physician 2006;74: Memis D, Inal MT, Kavalci G, et al. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care 2010;25: Pettersson PH, Jakobsson J, Owall A. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2005;19:306 9.

7 INTRAVENOUS ACETAMINOPHEN Herring et al 33S 4. Pergolizzi JV, Raffa RB, Tallarida R, et al. Continuous multimechanistic postoperative analgesia: a rationale for transitioning from intravenous acetaminophen and opioids to oral formulations. Pain Pract 2012;12: White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg 2005;101(5 Suppl):S Macario A, Royal MA. A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain. Intravenous Acetaminophen Studies. Pain Pract 2011;11: American Society of Anesthesiologists Task Force on Acute. Pain management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012;116: Calderon M, Castorena G, Pasic E. Postoperative pain management after hysterectomy a simple approach. In: Al-Hendy A, Sabry M, eds. Hysterectomy. InTech; Available from Accessed June 16, Miller E. The World Health Organization analgesic ladder. J Midwifery Womens Health 2004;49: Cadence Pharmaceuticals. Ofirmev (acetaminophen intravenous) package insert. San Diego, CA; 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: GlobalRPh. Opioids equianalgesic dosages. Available from Accessed June 16, Alhashemi JA, Alotaibi QA, Mashaat MS, et al. Intravenous acetaminophen vs oral ibuprofen in combination with morphine after cesarean delivery. Can J Anaesth 2006;53: Grundmann U, Wornle C, Biedler A, et al. The efficacy of the non-opioid analgesics parecoxib, paracetamol and metamizol for postoperative pain relief after lumber microdiscectomy. Anesth Analg 2006;103: Chrysostomou C1, Schmitt CG. Dexmedetomidine: sedation, analgesia and beyond. Expert Opin Drug Metab Toxicol 2008;4: