1 1 Intravenous Acetaminophen: A Review Alana Greenberg, RN, BSN Renee M. Whiton, RN, BSN Karen S. Dunn, PhD, RN Oakland University School of Nursing 402 O Dowd Hall Rochester, MI Telephone: (248) FAX: (248) Alana Greenberg is a student at Oakland University Beaumont Graduate Program of Nurse Anesthesia, Royal Oak, Michigan. Renee Whiton is a student at Oakland University Beaumont Graduate Program of Nurse Anesthesia, Royal Oak, Michigan. Karen S Dunn is an Associate Professor in the School of Nursing at Oakland University, Rochester, MI. Keywords: acetaminophen, analgesia, postsurgical pain
2 2 Abstract The purpose of this comprehensive review of the literature was to determine the efficacy and risks of adverse effects with the use of IV acetaminophen for postsurgical pain management Intravenous (IV) acetaminophen is a newly approved analgesic agent in the United States. Compared to the rectal and oral forms of acetaminophen that are used in the postsurgical setting, the IV formulation offers the advantage of providing fast onset analgesia and predictable plasma levels. The drug is associated with minimal side effects, as compared to other non-opioid analgesics, and can be used in almost any patient population. IV acetaminophen has been proven to decrease postoperative pain and improve patient satisfaction. Although it has only been shown to decrease opioid consumption postoperatively in some cases, it has been shown to decrease sedation levels and increase readiness for discharge. Further research can highlight its cost saving abilities with regards to earlier discharge and fewer unanticipated hospital admissions due to opioid related complications such as increased levels of sedation.
3 3 INTRAVENOUS ACETAMINOPHEN: A REVIEW Effective pain control in the postoperative period is essential for optimal recovery. Adequate postsurgical pain increases patient satisfaction, improves sleep, results in a more rapid recovery and shorter hospital stay, and lowers the risks of postoperative complications, such as the development of a deep vein thrombosis and pulmonary effects. 1 There are many different drugs that can be used to treat postoperative pain; each with its own risk of adverse effects. Determining what analgesic medications will provide adequate postsurgical pain management with the least amount of adverse effects however, continues to be a challenge for most health care providers. Throughout the decades, modalities to facilitate analgesia have been implemented with a variety of results. One of the most common ways of providing analgesia is with the use of opioids. Recently, it has been reported that the use of opioids has decreased in the postoperative setting due to unwanted side effects (e.g., respiratory depression, sedation, nausea and vomiting, and slowed gastrointestinal functioning) leading to longer postoperative stays and delayed recovery. 2 The use of non-opioid analgesics as adjuncts to opioids or as stand-alone agents in providing analgesia are becoming feasible options, as more drugs with less adverse side effects are being developed. In 2010, intravenous (IV) acetaminophen was approved in the United States (US) for the management of pain and the reduction of fever. 3 Hence, the purpose of this comprehensive review of the literature was to determine the efficacy and risks of adverse effects with the use of IV acetaminophen for postsurgical pain management since it is a relatively new approach. Specifically, the aim of this review was to assist health care providers in making the best evidenced-based clinical decision in pain management strategies.
4 4 LITERATURE REVIEW Review of the literature was conducted using the following databases: CINAHL and Medline. The search criteria was limited to the English language and included published articles from Each database was searched using the following primary search key terms: Intravenous acetaminophen, paracetamol, postsurgical pain, and postoperative analgesia. Inclusion criteria included the use of IV acetaminophen and a randomized, double blind study comparing IV acetaminophen to a placebo or other drug. Studies using the prodrug, proparacetamol, were excluded. Forty two articles were reviewed, and twelve articles were selected based on relevance to the topic and use of IV acetaminophen in a randomized double blind study. Background Acetaminophen is an analgesic and antipyretic that has been available for years in oral and suppository formulations, which are not always appropriate for postsurgical use. Outside the US, acetaminophen is known as paracetamol 3 and has been used as a successful intravenous analgesic for over a decade. Prior to the development of paracetamol, propacetamol, an IV water-soluble pro-drug of acetaminophen was prescribed in Europe for the management of postsurgical pain. 6 Propacetamol however, had several negative properties; the medication had to be reconstituted into a solution, and reports of pain at the injection site. Propacetamol was also highly insoluble and unstable in aqueous solutions, so it was replaced with paracetamol, an improved ready-to-use formula. IV acetaminophen is a non-opioid analgesic and antipyretic that may result in improved pain management with a reduction of side effects associated with other analgesic alternatives. The drug is approved for use in children aged 2 to older adulthood. IV acetaminophen is manufactured by Cadence Pharmaceuticals in the US and is a clear, colorless,
5 5 preservative free injection. The drug is supplied in a 100 ml glass vial containing 1000 mg acetaminophen. Once opened, the vial should be used within 6 hours. The drug is infused intravenously over 15 minutes. Cadence Pharmaceuticals provides specific dosing instructions for all age groups. 3 For children ages 2 to 12 and adults weighing less than 50 kg, the recommended dose is 15 mg/kg every six hours or 12.5 mg/kg every four hours. The maximum single dose for children is 15 mg/kg and the maximum daily dose is 75 mg/kg per day. For adults and adolescents weighing over 50 kg, the recommended dose is 1000 mg every 6 hours or 650 mg every 4 hours. The maximum single dose for adults is 1000 mg and the maximum daily dose is 4000 mg. IV acetaminophen is metabolized by the liver and excreted in the urine. The drug should be avoided in patients with severe liver disease as toxic metabolites can accumulate and cause necrosis in the liver, most commonly after an overdose. Acetaminophen is not associated with any significant adverse effects and is not associated with the common serious side effects seen with opioids and NSAIDs. Adverse effects related to the use of IV acetaminophen are rare, less than 1 in 10,000 cases, and are usually mild and transient. 1 Single dose studies and repeated dose studies have shown the most common side effects to include headache, nausea, vomiting, and insomnia. 3 Studies show the overall incidence of these events to be similar in both the IV acetaminophen and placebo groups. The primary safety concern with acetaminophen is its potential to cause hepatic toxicity from toxic metabolites. While oral doses subject the liver to maximal amounts of acetaminophen, IV dosing exposes the liver to less acetaminophen because it avoids first pass liver metabolism. The dose is
6 6 distributed to the systemic circulation before being delivered to the liver, reducing the potential for hepatic injury and improving the safety profile compared with equivalent doses of oral acetaminophen. 1 In a randomized, double-blinded, placebo controlled study comparing acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery, Wininger et al 2 examined the frequency of liver function test (LFT) value elevations in subjects receiving IV acetaminophen versus a placebo. There were no hepatic adverse events reported in the study and the frequency of LFT elevations in the IV acetaminophen groups were similar to what was observed in the combined placebo group. Two subjects in the placebo group and 2 subjects in the IV acetaminophen group had alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values greater than three times the upper limit of normal range (ULNR). Both placebo subjects had values that were above ULNR at baseline while the IV acetaminophen subjects had elevated values at baseline. Numerous other placebo-controlled trials have proven that the frequency of ALT or AST elevations observed with IV acetaminophen were numerically lower than but not significantly different from that seen with placebo. 2 Oral and suppository formulations of acetaminophen are commonly used in the clinical setting. Oral routes of administration are not ideal for the postsurgical population as patients are often not able to tolerate oral medications due to nausea, vomiting, sedation, dysphagia, and malabsorption. IV formulations are important for the postsurgical management of pain because IV delivery has a fast and reliable onset of analgesia, reaching a clinical analgesic effect within 5 minutes 1 and reaching therapeutic plasma concentrations in 15 minutes compared with the 45 minute onset of oral acetaminophen. 4 IV administration offers an additional advantage over the oral route because patients do not have to be fully awake to receive the mediation, initiating
7 7 analgesic therapy at an earlier stage of the postoperative recovery period. A randomized, controlled trial comparing IV versus oral paracetamol demonstrated that dosing with IV paracetamol yielded therapeutic concentrations in more patients compared with oral dosing in the perioperative period. 5 The IV group also had higher plasma concentrations throughout the study compared with those given the oral drug. IV administration can be subsequently transitioned to oral delivery when a more rapid onset of analgesia is not needed and once the patient is able to tolerate oral medications. Rectally administered acetaminophen is commonly used in the pediatric population following surgery. Compared with oral and IV administration, rectal administration is associated with a slow and unpredictable absorption, and does not consistently produce a rapid onset of analgesia. Because of the delayed absorption, many clinicians suggest using higher doses when administering acetaminophen by the rectal route. Higher rectal doses however, may expose children to drug accumulation and possible toxicity. 1 Multimodal analgesia is an effective means of improving pain control. A combination of different analgesics, each with a different mechanism of action, is used for its synergistic effects to decrease the dose of any one particular medication and therefore decrease the incidence of that medication s adverse effects. Multimodal analgesia can reduce opioid consumption, minimize adverse events, improve pain relief, facilitate earlier recovery, and reduce hospitalization costs. 2 Opioids can be combined with non-opioid analgesics and regional anesthesia to provide better postoperative pain control and patient satisfaction. While opioids are highly effective in the treatment of acute pain, they are associated with dose dependent risks including nausea, vomiting, constipation, sedation, and respiratory depression. 2 Non-opioid oral analgesics include acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs). There are only two
8 8 approved IV non-opioid analgesics in the US; ketorolac and ibuprofen, both of which are NSAIDs. 2 While these drugs avoid many of the adverse effects caused by opioids, they are associated with their own adverse effects such as bleeding, gastric mucosal damage, and renal toxicity; factors that may limit their use in the postoperative setting. 2 The ideal postsurgical analgesic should provide effective pain relief, have a low incidence of adverse effects, have minimal impact on major organ systems, and have no significant interactions with other medications. 6 IV acetaminophen meets these criteria and is a beneficial adjunct to multimodal analgesia in the postoperative period. There are many different approaches to the treatment of postsurgical pain, all with their own negative and positive aspects. Postsurgical pain management is usually controlled by opioid analgesics and is sometimes combined with non-opioids to minimize unwanted opioid side effects. While opioids provide rapid analgesia, they are associated with negative properties. Opioid-based analgesia can cause sedation, dizziness, constipation, nausea, and vomiting, which may delay the patient from early mobilization and lead to more serious complications, such as the development of a deep vein thrombosis, ileus, and atelectasis. These unplanned complications may then delay discharge and lead to unplanned hospital admissions, increase hospital costs and decrease patient satisfaction. NSAIDs, such as ketorolac, are often given intraoperatively to decrease the amount of opioids needed. However, there are many instances when NSAIDs are not clinically appropriate in the postsurgical period. Such instances include surgeries with a high risk of postoperative bleeding (e.g., tonsillectomy cardiovascular, or gastrointestinal). 7 Regional anesthesia, which include spinals, epidurals, and peripheral nerve blocks, are another method of pain control that decreases the amount of opioids needed, thus reducing the incidence of associated adverse effects. There are many benefits to regional
9 9 anesthesia and several negative effects including nerve damage, paresthesias, local anesthetic toxicity, and pneumothorax. While regional anesthesia provides effective intraoperative pain control, additional analgesia is usually needed postoperatively. Acetaminophen has not been shown to cause the serious side effects that other methods of analgesia cause. IV acetaminophen is a promising new medication that has the potential to safely discharge patients home earlier so they can resume their normal activities of daily living. Efficacy of IV Acetaminophen Ten randomized, double blinded, placebo controlled studies were chosen to address the efficacy of IV acetaminophen. The studies primary endpoints were patient pain scores from a range of fifteen minutes postoperatively to forty-eight hours postoperatively. The studies assessed postoperative pain after surgeries that produced pain in a range from mild to severe. Nine out of the ten studies found a statistically significant reduction in pain scores in the IV acetaminophen group compared to the placebo group. 2,6,8-14 An additional randomized, doubleblind, double-dummy, clinical study compared the postoperative analgesic effects of IV acetaminophen to meperidine. Findings reported from this study suggested that, when compared with meperidine, IV acetaminophen did not have a better analgesic effect. Pain scores were higher in the IV acetaminophen group. 15 Cakan et al 16 studied the effect of postoperative intravenous acetaminophen combined with morphine versus morphine alone among lumbar laminectomy and discectomy surgical patients and found statistically significant decreases in pain scores in the IV acetaminophen group combined with morphine versus morphine alone. Postoperative pain scores were also decreased in a study comparing IV acetaminophen as an adjunct to meperidine versus a group receiving only meperidine after major surgery. 17
10 10 Opioid Sparing Effect of IV Acetaminophen A secondary endpoint discussed in many of the studies was whether IV acetaminophen had an opioid sparing effect. Of the studies reviewed, five studies showed a statistically significant decrease in opioid consumption in the postoperative period. 2,8-11,17 Conversely, five studies did not find a statistically significant opioid sparing effect of intravenous acetaminophen compared to the placebo group. 6,12-14,16 Intravenous Acetaminophen and Adverse Effects Side effects and other areas of interest, such as nausea and vomiting, level of sedation, discharge time, and postoperative care unit recovery times were assessed in all of the studies reviewed. Six studies did not show any statistically significant increases or decreases in adverse effects between the intravenous acetaminophen group and the placebo group. 2,6,9-12 Cakan et al 16 found a statistically significant decrease in the number of patients suffering from postoperative vomiting in the intravenous acetaminophen group compared with the placebo group. When Arici, et al 9 looked at the incidence of nausea, vomiting, and itching between the IV acetaminophen group and the control group, the IV acetaminophen group had statistically significant decreased incidences of the adverse effects. Statistically significant decreases in nausea and vomiting were also found in a study by Memis et al 17 in the IV acetaminophen and meperidine group compared to the meperidine group alone. Salihoglue et al 13 also looked at the incidence of adverse events among the IV acetaminophen group and the control group and found a shorter duration of stay in the recovery room, shorter awakening times, and faster extubation times in the IV acetaminophen group. Additionally, researchers investigating length of hospital stay after total abdominal hysterectomy found a statistically significant shorter duration of hospital stay in the intravenous acetaminophen group compared to the placebo group. 8 Alhashemi and Daghistani 15
11 11 assessed sedation levels and time to discharge after pediatric dental restoration and found that the IV acetaminophen group had lower levels of sedation as well as earlier readiness to discharge compared to the meperidine group. Patient Satisfaction with Intravenous Acetaminophen Five of the twelve studies addressed patient satisfaction with their postoperative analgesia. Four of the studies found increased patient satisfaction among the patients who received intravenous acetaminophen compared to the patients who were in the control group. 2,6,8,16 Brodner et al 9 found there to be no difference among the groups in regard to satisfaction with their pain treatment postoperatively. Discussion Based on this literature review, these authors conclude that IV acetaminophen is an effective postsurgical analgesic with minimal risk for adverse effects. Although the study comparing meperidine to IV acetaminophen did not produce lower pain scores in the IV acetaminophen group, that study did find that the IV acetaminophen group had lower sedation levels and earlier readiness to discharge, potentially decreasing the time spent in the postoperative area 15. In addition, while there were only two studies comparing the use of IV acetaminophen as an adjunct to opioids, these studies did highlight the effectiveness of IV acetaminophen as an adjunct agent in reducing postoperative pain. Due to IV acetaminophens low levels of adverse effects, it is an appropriate analgesic for almost all patients and provides a stable plasma level of the drug based on dosing. Although fifty percent of the studies did not show a statistically significant decrease in opioid consumption postoperatively, some studies did show a decrease in other side effects, such as nausea and vomiting. In addition, a few studies highlighted the earlier readiness for discharge and decreased
12 12 levels of sedation after IV acetaminophen usage. This has the potential for cost savings to both the hospital and patient because of reductions in complications and earlier discharge rates. Overall, although only five studies addressed patient satisfaction with IV acetaminophen, the outcomes were promising. Increased patient satisfaction with pain management is an integral component of a patients overall rating of their hospital experience. More research is needed however, regarding the optimal time for dosing of IV acetaminophen to receive the greatest opioid sparing effect (reference?). Findings from these studies may lead to a reduction in the amount of opioids needed for pain relief and subsequently a decrease in adverse effects associated with opiods. More research is also needed regarding the impact of IV acetaminophen on discharge time from the postoperative care unit and its effect on decreasing length of hospital stay (reference?). This area of research has the potential to highlight the cost saving effect of IV acetaminophen. For now, the safety and effectiveness of IV acetaminophen has been reported in a number of randomized clinical trials. It has been found to be an appropriate analgesic agent in almost all patient populations. It is an effective analgesic in reducing pain scores postoperatively, and has increased patient satisfaction. Further research will provide additional support for its use postsurgically to highlight its ability to reduce pain and shorten discharge times resulting in cost savings.
13 13 Table 1: Summary of Studies from Literature Review Publication: 1 st Author/Year Surgery Model Authors Findings Brodner 2011 Minor-to-intermediate surgery 1 o Endpoints: Less postoperative surgical pain in IV acetaminophen group than placebo group 2 o Endpoints: No difference in patient satisfaction among groups, No opioid sparing effect, No difference in rate of adverse effects among groups Alhashemi 2007 Dental Restoration 1 o Endpoints: Meperidine group had lower postoperative pain scores than IV acetaminophen group 2 o Endpoints: Acetaminophen group earlier readiness for discharge, less sedation than meperidine group Atef 2007 Tonsillectomy 1 o Endpoints: IV acetaminophen group experienced less pain postoperatively than placebo group 2 o Endpoints: Opioid sparing effect Dilmen 2010 Lumbar Disc Surgery 1 o Endpoints: Less postoperative pain in IV acetaminophen group compared to placebo group 2 o Endpoints: No difference in opioid consumption, No difference in rate of adverse effects among groups Ohnesorge 2009 Breast Surgery 1 o Endpoints: Decrease in postoperative pain in IV acetaminophen group compared to placebo 2 o Endpoints: No opioid sparing effect, No difference in rate of adverse effects amount groups Kemppainen Endoscopic Sinus Surgery 1 o Endpoints: Lower pain scores in IV acetaminophen group compared to placebo group 2 o Endpoints: Significant opiod sparing effect, No difference between groups in terms of adverse effects Memis 2010 Major Surgery 1 o Endpoints: Decreased postoperative pain scores in Meperidine and IV acetaminophen group compared to Meperidine alone group 2 o Endpoints: Decease in nausea and vomiting in IV acetaminophen group, opioid sparing effect of IV acetaminophen Arici 2009 Total Abdominal Hysterectomy 1 o Endpoints: Decreased postoperative pain in IV acetaminophen group compared to placebo 2 o Endpoints: Opioid sparing effect, Decreased incidence of nausea and vomiting and itching
14 14 in acetaminophen group, Shorter hospital stays among patients in IV acetaminophen group compared to placebo group Wininger 2010 Abdominal Laparoscopic Surgery 1 o Endpoints: Lower pain scores among IV acetaminophen group compared to placebo group 2 o Endpoints: Opioid sparing effect, Patient satisfaction scores higher in IV acetaminophen group, No difference in incidence of adverse effects among groups Sinatra 2005 Major Orthopedic Surgery 1 o Enpoints: Pain relief scores were higher among IV acetaminophen group compared to placebo group 2 o Endpoints: Opioid sparing effect, Higher patient satisfaction among IV acetaminophen group, No reduction in adverse effects Cakan 2008 Lumbar Laminectomy and Discectomy 1 o Endpoints: Lower pain scores in the IV acetaminophen with morphine group compared to the morphine alone group 2 o Endpoints:Less vomiting postoperatively in IV acetaminophen with morphine group compared to morphine group, Higher patient satisfaction scores in IV acetaminophen group, Salihoglu 2009 Laparoscopic Cholecystectomy 1 o Endpoints: Lower pain evaluation scores among IV acetaminophen group compared to placebo group 2 o Endpoints: Opioid sparing effect, Shorter duration of stay in the recovery room, shorter awakening times, and faster extubation times in the IV acetaminophen group
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