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Authors; Kendra Brett, and Melissa Severn.
Pain is 1 of the most common reasons patients use the emergency department (ED). In Canada, pain occurring in the abdomen, pelvis, throat, chest, or back were some of the most frequent reasons for patients to use the ED in 2022 to 2023.1 Unfortunately, not all patients report receiving adequate pain relief in the ED. In a 2007 study from Canada and the US, 40% of patients presenting to the ED with severe acute pain did not receive analgesics, and over 70% of patients were discharged while still experiencing moderate to severe pain.2
For patients experiencing pain due to trauma, adequate pain management can improve patient comfort, reduce the stress response, and potentially reduce the risk of acute pain developing into chronic pain.3 Failure to provide adequate treatment for patients experiencing acute pain in the ED has the potential to decrease patient comfort, impact length of stay in the hospital, impair quality of life, increase the risk of complications, or delay returning work.4
Pain management aims to achieve a level of pain that the patient finds tolerable and allows them to function.4 For the management of moderate to severe acute pain in the ED, drugs should be effective, easy to administer, and have limited side effects.4 These drugs include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen), and opioids, which may be administered using different routes (e.g., oral, IV, intramuscular).4 As of 2019, oxycodone and hydromorphone were the most commonly prescribed opioids for moderate to severe pain in Canada.5 Opioids can be associated with adverse effects, including high blood pressure, changes in mental status (e.g., delirium), itchiness, nausea, and vomiting,6 and the misuse of opioids can lead to opioid use disorder.7 NSAIDs can also be associated with adverse effects, such as gastrointestinal effects (e.g., peptic ulcer), high blood pressure, or a risk of bleeding.8
Acetaminophen is a drug that provides pain relief and reduces fever; it can be administered orally, rectally, or intravenously.9 Acetaminophen injection is a sterile solution administered through IV infusion (herein called IV acetaminophen). It is indicated for the short-term management and treatment of mild to moderate pain, moderate to severe pain with adjunctive opioid analgesics, and fever.10 It is approved by Health Canada for use in patients 2 years of age or older.10 According to the product monograph, the most common adverse events from IV acetaminophen include nausea, vomiting, headache, and constipation, which are predominantly mild to moderate in severity.10 Assuming IV acetaminophen provides comparable pain relief and safety profile compared to IV opioids or IV NSAIDs, it has the potential to be an alternative analgesic drug in the ED for patients with moderate to severe pain.
The IV route for acetaminophen has been proposed as an alternative to oral acetaminophen due to the potential that it may provide more rapid and more predictable acetaminophen analgesia.11 IV acetaminophen could also be an alternative for patients who cannot take oral medications. However, the cost of IV acetaminophen is often substantially higher for pediatric and adult patients when compared to oral (tablet or liquid) or rectal formulations of acetaminophen.12,13 Thus it is important to evaluate both the clinical effectiveness and the cost-effectiveness of IV acetaminophen.
To support decision-making about the use of IV acetaminophen in the ED, this Rapid Review summarizes and critically appraises the available clinical and cost-effectiveness studies and evidence-based guidelines on the use of IV acetaminophen use for patients experiencing moderate to severe pain in the ED.
An information specialist conducted a literature search on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, and the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were IV acetaminophen and ED settings. The search was completed on August 24, 2023, and limited to English-language documents.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1 or they were duplicate publications. Studies were excluded if they evaluated concurrent IV acetaminophen and opioid. We excluded systematic reviews (SRs) in which all relevant studies were captured in other more recent or more comprehensive SRs and primary studies retrieved by the search if they were captured in 1 or more included SRs. If an SR did not provide sufficient detail about the findings in the relevant primary studies, we excluded the SR and included the relevant primary studies. Guidelines with an unclear methodology were also excluded.
The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)14 for SRs, the Downs and Black checklist15 for randomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument16 for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
This report includes 3 SRs,11,17-19 5 randomized controlled trials (RCTs),20-24 and 1 evidence-based guideline.25 Study selection details are presented in Appendix 1. Additional references of potential interest are provided in Appendix 6.
One additional SR (Sin et al.19) was identified. This SR searched the literature until July 2015 and included studies that compared IV acetaminophen to IV opioids, IV NSAIDS, or placebo in patients of any age in the ED with moderate to severe acute pain.19 It included 9 relevant RCTs, of which 8 RCTs overlapped with the SR by Quereshi et al.17 The remaining relevant RCT was not reported with sufficient detail in the SR by Sin et al.;19 thus, the primary study (Oguzturk et al.)24 was included instead of the SR.
Detailed characteristics of the included publications are provided in Appendix 2. Two of the SRs17,18 included overlapping primary studies, with 10 out of the 11 studies in the 2019 SR18 included in the more comprehensive 2023 SR17 (refer to Appendix 5 for details regarding overlap). To avoid duplication of results, information from individual primary studies is only reported once.
We identified 3 SRs11,17-19 and 5 RCTs20-24 to address this research question, comparing IV acetaminophen with oral acetaminophen,11,16,20 IV NSAIDS,17,22 IV opioids,17,18,21,23,24 and placebo.24
One SR11 had broader inclusion criteria than the present review. Specifically, this SR searched for studies in children younger than 18 years with pain or fever in any setting, and assessed clinical effectiveness, pharmacokinetics, and cost of IV acetaminophen. It included studies published up to October 2019; however, none of the included studies were relevant to this report (i.e., none of the studies evaluated the clinical effectiveness of IV acetaminophen compared with oral acetaminophen for moderate to severe pain in the ED setting).
One RCT20 included 180 adults in the ED with moderate to severe pain due to a femur fracture and compared 1,000 mg of IV acetaminophen to 1,000 mg of oral acetaminophen. Patients were followed for 4 hours, and the outcomes included pain, the requirement for rescue analgesia, and adverse events.
One SR with meta-analysis17 searched for studies in adults attending the ED with acute pain published up until May 2022, and identified 12 RCTs with relevant comparisons between IV acetaminophen and IV NSAIDs. The scope of this SR was broader than that of this report in terms of the level of pain (i.e., they did not limit the patients to those with moderate to severe pain) and comparators (i.e., they also included intramuscular NSAIDs). While all the patients in the IV NSAIDs RCTs had moderate to severe pain at baseline, some of the relevant meta-analyses combined studies that used intramuscular NSAIDs with studies that used IV NSAIDs as the comparator.
One RCT22 included 210 adults with acute low back pain in the ED with pain severity that was moderate or higher. Patients were treated with 1,000 mg IV acetaminophen, 50 mg IV dexketoprofen, or 400 mg IV ibuprofen and followed for 60 minutes.
Relevant outcomes for the SR and the RCT were pain, the need for rescue analgesia, and adverse events.17,22
Another SR18 searched for studies in adults and pediatric patients with acute moderate to severe pain published through May 2019. It did not identify any unique primary studies comparing IV acetaminophen with IV NSAIDs; thus, this SR did not contribute any findings to this comparison.
Two SRs17,18 included RCTs that compared IV acetaminophen to IV opioids. The SR with meta-analysis by Qureshi et al.17 included 18 RCTs in adults with acute pain in the ED with relevant comparisons between IV acetaminophen and IV opioids. As the population of interest to this SR was broader than the current review in terms of pain severity, in the meta-analysis there is 1 RCT for which the baseline pain is unclear and another RCT in which the mean pain for patients who received IV acetaminophen was mild whereas the mean pain for the patients who received the opioids was moderate. The SR by Sobieraj et al.18 identified 10 RCTs relevant to this report, 9 of which were also included in the Qureshi et al. SR.17 The remaining RCT in the Sobieraj et al. SR included 55 people aged 15 to 60 (mean age of 35 years) and patients received either 1,000 mg IV acetaminophen or 0.1 mg/kg IV morphine.
Three RCTs21,23,24 compared IV acetaminophen to IV opioids with moderate to severe pain in the ED. The RCTs included 162 adults 65 years or older,21 220 adults between 21 and 64 years,23 and 140 patients 17 years or older.24 Two of the RCTs used 1,000 mg IV acetaminophen compared to IV hydromorphone (0.5 mg21 or 1 mg23) and the other RCT compared 15 mg/kg IV acetaminophen against 1 mg/kg IV tramadol.24
Relevant outcomes for the SRs and the RCTs were pain,17,18,21,23,24 the need for rescue analgesia,17,21,23 and adverse events.17,18,21,23,24
One of the included RCTs24 also included a comparison between 15 mg/kg IV acetaminophen and placebo in patients 17 years or older with severe abdominal pain in the ED. This study included 70 patients per group (mean age 32), followed patients for 40 minutes, and assessed pain and adverse events.
No relevant studies were identified for question 2; therefore, no summary can be provided.
One evidence-based guideline25 provided recommendations regarding the use of IV acetaminophen in the ED setting. This 2023 guideline was developed by a technical expert panel of emergency medicine clinicians in the US to provide guidance for the use of analgesics for treating patients with moderate to severe pain in the ED. The guideline followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework to develop the recommendations26 using evidence identified in a 2019 SR,18 which is also included in this report. The GRADE framework was also used to rate the strength of the evidence (from very low to high quality) and to classify the strength of the recommendations (strong or conditional).
Critical appraisal summaries are organized by research question, comparison (where appropriate), and study design. For the SR that did not contain any relevant primary studies, only the relevant items from the AMSTAR 2 tool were assessed.
Additional details regarding the strengths and limitations of the included publications are provided in Appendix 3.
The SR on IV acetaminophen in pediatric patients11 clearly stated the population, intervention, comparator, and outcomes of interest and registered its protocol a priori, thus reducing the risk of reporting bias. Although no primary studies relevant to the current Rapid Review were identified, the authors of this SR used a comprehensive search strategy (i.e., searched 5 databases, provided the full search strategy, and searched references lists of relevant publications) and study selection was performed in duplicate, reducing the likelihood that relevant literature was missed. However, the authors did not justify why they restricted the studies to those published in English, thus it is unknown whether relevant studies in other languages were missed.
Strengths of the RCT by Francheschi et al.20 included a good description of the aim, the outcomes, and the interventions; reporting simple outcomes data and actual P values; and appropriate statistical tests were used to compare the main outcomes. The patients were described with limited detail, with baseline pain only reported in a figure, thus making the variation in baseline pain between groups difficult to determine. In addition, confidence intervals were not reported for the main outcomes, thus limiting the certainty in these findings. Insufficient details were reported regarding the methods of randomization and allocation concealment, and it is unclear whether the study is at risk of selection bias. In addition, it was unclear why the authors randomized the patients in a 5 to 1 ratio of IV versus oral acetaminophen, or whether the authors accounted for this ratio when they conducted the sample size calculation. Due to the nature of the interventions (i.e., IV versus oral acetaminophen), it was not possible to blind the patients to the intervention (which suggests a risk of performance bias), and it was not reported whether there was an attempt to blind the researchers assessing the main outcomes to the interventions (which could mean a potential risk of detection bias). The authors used a validated visual analogue scale (VAS) for pain but it was not reported whether the primary outcome (i.e., at least a 1 point reduction in VAS at 1 hour, on a 10-point scale) represents a minimally important difference (i.e., the smallest improvement considered worthwhile by a patient) in this specific population.
Two SRs17,18 were included that searched for studies comparing IV acetaminophen to IV NSAIDs. The SR by Sobieraj et al.18 did not contribute unique primary studies for this comparison to this review, thus the summary of the critical appraisal is in the Studies Comparing IV Acetaminophen to IV Opioids section.
The SR by Qureshi et al.17 clearly stated the population, intervention, comparator, and outcomes of interest and registered its protocol a priori, thus reducing the risk of reporting bias. A comprehensive search strategy was used and study selection and data extraction were performed in duplicate, thus reducing the likelihood that relevant studies were missed or that there were errors in data extraction. For the individual primary studies in the SR, baseline pain scores were not reported, but the populations were adequately described, and the interventions, comparators, and outcomes were well described. The authors used appropriate tools to assess the risk of bias of the included studies and to assess the quality of the evidence by outcome; however, they did not account for risk of bias in the meta-analysis, nor did they discuss the potential impact of the risk of bias or the quality of the evidence on the findings, and the potential impact is unclear. There is also considerable statistical heterogeneity in the meta-analyses, which the authors explored using subgroup analyses by type of pain and by specific NSAID (not reported in this Rapid Review). The reporting of the findings was unclear, with some discrepancies between the findings reported in the main publication and the appendices, which limits the certainty in the findings.
Strengths of the RCT by Dogan et al.22 include a good description of the aim of the study, the inclusion criteria, the outcomes, and the interventions, as well as reporting the patients’ baseline levels of pain, and simple outcomes data. The methods of randomization and allocation concealment were appropriate, which reduced the risk of selection bias. The patients, those administering the medications and those assessing the outcomes, were blinded to the interventions, reducing the risk of performance and detection bias. Limited information is reported about the patients (e.g., age is not reported and sex is not reported by group), and the statistical analysis did not adjust for any potential confounders (e.g., the difference in baseline pain between the groups) thus reducing our understanding of the potential impact of confounding factors. It was unclear whether any patients were lost to follow-up as the reporting of the number of people randomized to each intervention group was unclear, with the text and the patient flow diagram reporting different numbers. The authors used a validated VAS for pain to assess pain, but they did not specify what was considered a minimally important improvement in pain for this population, thus limiting the understanding of the clinical implications of the findings.
Two SRs17,18 were included that searched for studies comparing IV acetaminophen to IV opioids. The summary of the critical appraisal of the SR by Qureshi et al.17 is in the Studies Comparing IV Acetaminophen to IV NSAIDs section.
The SR by Sobieraj et al.18 clearly stated the population, intervention, comparator, and outcomes of interest and registered its protocol a priori, thus reducing the risk of reporting bias. A comprehensive search strategy was used and study selection was performed in duplicate, thus reducing the likelihood that relevant studies were missed. Data extraction was performed by 1 reviewer and verified by a second reviewer, thus limiting the possibility of errors in data extraction. The included studies were well described in terms of population, interventions, comparators, and outcomes; an appropriate tool was used to assess the risk of bias of the included studies; and the authors considered the certainty of the evidence when interpreting the findings.
Three RCTs21,23,24 were included that compared IV acetaminophen to IV opioids. The aim of study, the interventions, and the eligibility criteria for patients were well described in all 3 RCTs. Across the RCTs, there were minimal or no losses to follow-up and the methods of randomization and allocation concealment were sufficient to reduce the risk of selection bias. The patients and those administering the medications were blinded in all 3 RCTs (reducing the risk of performance bias) and in 1 RCT23 those assessing the outcomes were also blinded to the intervention (reducing the risk of detection bias). In 2 RCTs21,23 the main outcomes are well described and well reported, including simple outcome data, mean differences between groups, and 95% confidence intervals. In the RCT by Oguzturk et al.,24 the authors reported P values and the median plus the range of the VAS scores at various time points, but did not report confidence intervals, nor the mean difference between time points by intervention groups, nor did they compare the change in pain score between groups, thus limiting the interpretation of the findings. Furthermore, this RCT24 did not specify what was considered a minimally important improvement in pain for this population, and it is unclear whether appropriate statistical tests were used to assess the main outcomes (e.g., t tests used to assess differences between 3 groups for some outcomes), which further limits the interpretation of this study’s findings. In the other 2 RCTs21,23 the authors specified the minimally important improvement in pain and the results focused on whether the interventions achieved this improvement in pain.
One RCT by Oguzturk et al.24 included a comparison between IV acetaminophen and placebo. This study also included a comparison between IV acetaminophen and opioids, and the summary of the critical appraisal is in the Studies Comparing IV Acetaminophen to IV Opioids section.
The guideline25 had a clear objective, described the population and target users of the guideline, and reported the health questions covered by the guideline. The recommendations were specific and easily identifiable. The names, affiliations, and areas of expertise were provided for the guideline development group members, who were from relevant professional groups. Systematic methods were used to identify the evidence informing the recommendations (published in a separate SR18). The methods used to synthesize the evidence and to develop the recommendations were clearly described in the companion methods paper,26 and the guideline development group considered the health benefits and side effects, as well as certainty of evidence, values, resources required, cost-effectiveness, equity, acceptability, and feasibility when formulating the recommendations. The authors provide a summary of the evidence that supports each recommendation, and there is a clear link between the recommendations and supporting evidence. However, while the main guideline publication indicates that the companion paper includes the summary of findings tables and the evidence-to-decision tables, no supplementary files or appendices were found for the companion paper, thus we were unable to review these evidence tables. It was not reported whether the recommendations were externally validated by experts; however, it is likely that the guideline underwent peer review before its publication. Fourteen authors declared no conflicts of interest and 1 author declared receiving an honorarium for their work on the project. The source of funding was declared, and an explicit statement was made that the authors had editorial independence from the funding organizations.
Appendix 4 presents the main study findings.
There was some overlap in the primary studies included in the SRs17,18 (refer to Appendix 5); therefore, to avoid duplication of results, outcomes data from individual primary studies are only reported once.
One RCT20 was identified that examined the clinical effectiveness of IV acetaminophen compared to oral acetaminophen.
In adults in the ED with moderate to severe pain due to a femur fracture, IV acetaminophen reduced pain in a significantly greater proportion of patients at 1 hour compared to oral acetaminophen, but there was no difference in pain relief between the groups at 4 hours.20
A greater proportion of adults who received IV acetaminophen required rescue therapy at 4 hours compared to those who received oral acetaminophen (17.5% and 3.7%, respectively), but the difference was not statistically significant.20
No adverse events were reported within 4 hours of adults receiving IV acetaminophen or oral acetaminophen.20
One SR17 and 1 RCT22 were identified that examined the clinical effectiveness of IV acetaminophen compared to IV NSAIDs. Within the SR,17 the authors assessed the evidence to be low quality for pain, the need for rescue analgesia, and adverse events.
One SR with meta-analysis17 compared the analgesic effects of IV acetaminophen to NSAIDs (either IV or intramuscular administration) in adults with moderate to severe pain. This study reported:
One RCT22 compared IV acetaminophen with 2 different IV NSAIDs (dexketoprofen and ibuprofen) in patients with acute low back pain and reported no differences in mean pain reduction between the 3 groups at 30 minutes or 60 minutes.
One SR with meta-analysis17 that compared IV acetaminophen to NSAIDs (either IV or intramuscular administration) in adults with moderate to severe pain reported the following:
In patients with acute low back pain, 1 RCT reported that no patients required rescue analgesia after 60 minutes in either the IV acetaminophen group or the IV NSAID group (dexketoprofen or ibuprofen).22
Two SRs17,18 and 3 RCTs21,23,24 were identified that examined the clinical effectiveness of IV acetaminophen compared to IV opioids. The authors of 1 SR17 assessed the evidence to be low quality for pain and the need for rescue analgesia, and moderate quality for adverse events.
In adults with moderate to severe pain in the ED, most of the identified evidence did not report significant differences in pain between IV acetaminophen and IV opioids. Specifically, 1 SR with meta-analysis found no evidence of a difference in pain reduction at 30 minutes, 60 minutes, or 120 minutes when IV acetaminophen was compared with IV opioids.17 One additional RCT also reported no difference in pain at 20 minutes or 40 minutes (results of statistical test not reported).24
Of the remaining identified evidence that addressed pain, 3 RCTs reported that IV opioids reduced pain statistically significantly more than IV acetaminophen at 30 minutes (1 RCT from 1 SR)18 or 60 minutes.21,23 However, the difference in pain reduction between the treatments was only clinically meaningful to patients in 1 RCT23 (the difference was not clinically meaningful in the RCT21 and not reported in the other RCT18).
When adults with moderate to severe pain in the ED were treated with IV acetaminophen compared with IV opioids, 3 studies found no difference in the requirement for rescue analgesia within 30 minutes (SR with meta-analysis)17 or within 60 minutes (2 RCTs).21,23 When patients were asked whether they would like additional analgesia at 60 minutes, a significantly higher proportion of patients in the IV opioid group declined additional analgesia (1 RCT).23
In adults with moderate to severe pain in the ED, most of the identified evidence reported a safety benefit for IV acetaminophen compared with IV opioids. Specifically, 1 SR with meta-analysis found that those treated with IV acetaminophen had significantly fewer adverse events than those treated with IV opioids17 and 1 RCT reported significantly fewer cases of nausea and a nonsignificant trend toward fewer cases of vomiting in those treated with IV acetaminophen.23
Of the remaining evidence that addressed safety outcomes, 4 RCTs reported no statistically significant difference in adverse events,21 dizziness (1 RCT from 1 SR),18 nausea or vomiting,24 or pruritus.23
One RCT24 was identified that examined the clinical effectiveness of IV acetaminophen compared to placebo.
Compared to those who received a placebo, patients with severe abdominal pain who received IV acetaminophen experienced a greater decrease in pain at 20 minutes and 40 minutes (statistically significant differences; 1 RCT).24
In patients with severe abdominal pain, 18.6% of patients who received IV acetaminophen experienced nausea or vomiting after 40 minutes, and no patients who received the placebo experienced nausea or vomiting (1 RCT).24
No relevant evidence was identified regarding the cost-effectiveness of IV acetaminophen use for patients experiencing moderate to severe pain in the ED setting; therefore, no summary can be provided.
In the ED, for the initial management of moderate to severe pain, the following is recommended in 1 guideline:25
No evidence was found for the following; therefore, no conclusions can be formed on these research questions:
While we identified 1 SR11 that searched for studies specifically comparing IV acetaminophen to oral acetaminophen in pediatric patients, and another SR18 that searched for studies of IV acetaminophen compared to IV opioids or IV NSAIDS in people of any age, neither SR identified any relevant primary studies exclusively focused on pediatric patients. One relevant primary study in the Sobieraj et al. SR18 included patients between 15 and 60 years of age, but the mean age of the population was 35; thus, no conclusions can be drawn regarding pediatric patients from this study.
There was limited evidence for some comparisons, with 1 RCT20 comparing IV acetaminophen to oral acetaminophen and 1 RCT24 comparing IV acetaminophen to placebo, potentially limiting the reliability of these findings.
None of the studies reported length of stay in the ED as an outcome, thus no conclusions can be formed on the impact of IV acetaminophen on this outcome.
None of the included studies were conducted in Canada and the guideline25 was developed for the US, which may limit the generalizability of the findings of this Rapid Review to the Canadian health care context. One SR11 was conducted by authors from Canada, but this SR did not include any primary studies relevant to this report.
The specific opioids and NSAIDs used in the studies may also limit the generalizability of the findings to the Canadian health care context if the specific drugs or formulations are not available in Canada. For the IV opioid comparison, IV tramadol was the opioid used in 1 RCT24 and 2 of the studies in the SR by Qureshi et al.17 Health Canada only lists oral formulations of tramadol and does not list any IV formulations for tramadol on the Drug Product Database.27 For the IV NSAID comparison, IV dexketoprofen and IV ketorolac were used in 1 RCT22 and 8 of the studies in the SR by Qureshi et al.17 (6 RCTs used IV dexketoprofen and 2 RCTs used IV ketorolac). IV formulations of these specific NSAIDS are not listed on Health Canada’s Drug Product Database.27
There was considerable clinical heterogeneity in the evidence evaluating IV acetaminophen, as well significant statistical heterogeneity in the SR with meta-analysis.17 There was substantial heterogeneity in the indication causing the pain (e.g., fractures, low back pain, abdominal pain, migraine, dysmenorrhea, renal colic, pancreatis, nonspecific pain).17,18,20-24 In addition, while the majority of the studies included patients with moderate to severe pain, there were 2 primary studies within the SR with meta-analysis17 that included patients with low or unclear levels of pain.
In the SR with meta-analysis,17 the authors explored the statistical heterogeneity using subgroup analyses by type of and by specific NSAIDs, and results were generally consistent with the primary analyses showing no differences between groups. There was moderate to substantial statistical heterogeneity in the subgroup analyses by type of pain, and for back pain the reduction in pain was greater for IV opioids than for IV acetaminophen. However, there was no evidence of a difference for the other types of pain (i.e., renal colic, musculoskeletal injuries, abdominal pain, and headaches) when IV acetaminophen was compared to IV opioids or IV NSAIDS.17 In the subgroup analyses by type of NSAID, the reduction in pain was greater for IV ibuprofen than for IV acetaminophen, but there was no evidence of a difference for dexketoprofen or ketorolac.17
There was also heterogeneity in the dose of IV acetaminophen as well as the specific drugs and doses used as comparators. Six studies used a 1,000 mg dose of IV acetaminophen17,18,20-23 while 1 study used a dose of 15 mg/kg IV acetaminophen.24 The IV opioids included morphine, tramadol, fentanyl, and hydromorphone,17,18,21,23,24 and the IV NSAIDs included ibuprofen, dexketoprofen, and ketorolac.17,22 In addition, some of the meta-analyses in the SR combined studies that used intramuscular NSAIDs with studies that used IV NSAIDs as the comparator;17 thus, conclusions cannot be made about IV NSAIDs alone.
This report comprises 3 SRs11,17-19 and 5 RCTs20-24 regarding the clinical effectiveness of IV acetaminophen and 1 evidence-based guideline25 regarding the use of IV acetaminophen for patients experiencing moderate to severe pain in the ED. No relevant evidence was identified regarding the cost-effectiveness of IV acetaminophen in this population.
In adults with moderate to severe pain in the ED, limited evidence suggests that IV acetaminophen may offer an improvement in pain relief within the first hour of administration, but similar reductions in pain after 4 hours, when compared to oral acetaminophen (1 RCT).20 After 4 hours, a smaller, but not statistically significant, proportion of patients treated with oral acetaminophen required rescue analgesia (compared to IV acetaminophen),20 which may be due to the initially slower onset of pain relief provided by the oral formulation. As the need for rescue analgesia was not reported at different time points in this study, it is unknown whether similar findings for rescue analgesia would have been observed earlier than at 4 hours. No adverse events were reported following treatment with IV or oral acetaminophen. There were some limitations identified with this study (e.g., no confidence intervals reported, insufficient details about randomization, lack of blinding) which may limit the certainty of this evidence.
IV acetaminophen and IV NSAIDs provide clinically similar reductions in pain after 30 minutes in adults in the ED with moderate to severe pain.17,22 After 60 minutes, NSAIDs may offer a modestly greater improvement in pain relief than IV acetaminophen, but the difference is not clinically meaningful (1 SR),17 or they may provide similar pain relief (1 RCT).22 IV NSAIDs may offer more sustained pain relief, as patients treated with IV acetaminophen may experience a more frequent need for rescue analgesia (1 SR).17 However, in those with acute low back pain, no patients required additional analgesia with IV acetaminophen or IV NSAIDs (1RCT).22 The risk of adverse events was comparable between IV acetaminophen and IV NSAIDs (1 SR),17 with 1 study reporting no side effects from either drug.22 The authors of the SR17 assessed the evidence comparing IV acetaminophen to IV NSAIDs to be of low quality with significant heterogeneity, and there are some limitations in the RCT22 (e.g., minimal reporting of patient characteristics, uncertainty with the main outcome). These limitations should be considered when interpreting these findings.
The findings for pain relief were mixed, but most of the identified evidence comparing IV acetaminophen with IV opioids did not observe a clinically important difference or a statistically significant difference in pain between groups (1 SR with meta-analysis, 1 RCT).17,24 The remaining identified studies reported a statistically significant improvement in pain favouring IV opioids (but not a clinically meaningful difference; 1 RCT from 1 SR and 1 RCT),18,21 and 1 study reported a larger decrease in pain favouring opioids that is both clinically and statistically different (1 RCT).23 No difference was observed in the proportion of patients requiring rescue analgesia between IV acetaminophen and IV opioids within the first hour after treatment (1 SR, 2 RCTs).17,21,23 However, when patients were asked whether they would like additional analgesia at 60 minutes, a higher proportion of patients in the IV opioid group declined (1 RCT).23 Patients treated with IV acetaminophen experienced either fewer adverse events (2 SRs, 1 RCT)17,18,23 or a similar number of adverse events (3 RCTs)21,23,24 than those treated with IV opioids. The limitations of the evidence should be considered when interpreting these findings. Specifically, the authors of the SR17 assessed the evidence comparing IV acetaminophen to IV opioids to be of low quality for pain and the need for rescue analgesia, and of moderate quality for adverse events, as well as the specific limitations of the 3 RCTS21,23,24 (e.g., uncertainty in the statistical analysis, reporting of the main outcome).
Limited evidence suggests that IV acetaminophen provides greater pain relief in adults with severe abdominal pain, but may cause more patients to experience nausea and vomiting, compared to those who received a placebo (1 RCT).24
For the initial management of moderate to severe pain for patients in the ED, IV NSAIDs are recommended instead of IV acetaminophen (1 guideline).25 If IV acetaminophen is available, affordable, and easy to administer, then IV acetaminophen is recommended instead of IV opioids alone (1 guideline).25 These are both conditional recommendations, based on evidence with low certainty.
The authors of the SR with meta-analysis17 and the authors of the guideline25 both used GRADE to evaluate the strength of the evidence comparing IV acetaminophen to IV NSAIDs and IV opioids, and reported that the quality of the evidence was low17,25 or moderate (only for adverse events when compared to NSAIDs).17 Researchers should consider that the current findings related to the use of IV acetaminophen in the ED should be confirmed with additional well-conducted RCTs (e.g., with appropriate randomization procedures and blinding to reduce the risk of selection and performance bias) and SRs with meta-analysis. From the Canadian health care context, additional studies that compare IV acetaminophen to IV NSAIDs and IV opioids that are available for use in Canada are needed.
In addition, given the potentially higher cost of IV acetaminophen,12,13 research is needed to determine whether IV acetaminophen is cost-effective compared to the other available options for treating patients with moderate to severe pain in the ED. Studies specifically evaluating the effectiveness of IV acetaminophen compared to oral acetaminophen, IV opioids, or IV NSAIDs in pediatric patients with moderate to severe pain in the ED are also needed.
This report is focused of the use of IV acetaminophen for acute pain in the ED. Future research may consider the potential impacts of IV acetaminophen after the initial acute phase of treatment, such as the duration of analgesia required in the ED and the need for analgesia at discharge.
The findings for this report suggest that IV acetaminophen may initially offer an improvement in pain relief when compared to oral acetaminophen, but that both drugs offer similar reductions in pain over time.20 However, decision-makers should consider that patients treated with oral acetaminophen may be less likely to need rescue analgesia at 4 hours (possibly due to the initial slower onset of pain relief provided by oral acetaminophen), but the evidence is uncertain.20
In general, IV acetaminophen and IV NSAIDs provide similar reductions in pain and a comparable risk of adverse events in adults in the ED with moderate to severe pain.17,22 However, decision-makers should consider that there is the potential that IV NSAIDs offer a modest improvement in pain relief (statistically but not clinically significant difference) with fewer patients requiring rescue analgesia compared to IV acetaminophen.17 This aligns with the recommendation to use IV NSAIDs for initial pain management for patients with moderate to severe pain in the ED (1 guideline).25 When selecting a pain reliever, decision-makers must also consider the contraindications for use for the specific drug and ensure that it is appropriate for the patient.
There is the potential that IV opioids may offer an improvement in pain relief compared with IV acetaminophen;18,21,23 however, some studies reported no evidence of a difference between the treatments17,24 or a difference that is statistically different (favouring opioids) but not clinically meaningful.18,21 Decision-makers should also consider that IV opioids may be associated with an increased risk of adverse events, such as nausea and vomiting,17,18,23 with a comparable incidence of rescue analgesia, when compared to IV acetaminophen.17,21,23 In the included guideline, IV acetaminophen is recommended instead of IV opioids alone for treating patients with moderate to severe pain in the ED, if IV acetaminophen is available, affordable, and easy to administer in the ED (1 guideline).25
emergency department
grading of recommendations, assessment, development, and evaluation
nonsteroidal anti-inflammatory drug
randomized controlled trial
systematic review
visual analogue scale
Contributors: Elizabeth Carson, Shannon Hill, Farhana Shivji.
Selection of Included Studies.
Characteristics of Included Systematic Reviews.
Characteristics of Included Primary Clinical Studies.
Characteristics of Included Guideline.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Systematic Reviews Using AMSTAR 2.
Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist.
Strengths and Limitations of Guideline Using AGREE II.
Note that this appendix has not been copy-edited.
Summary of Findings by Comparison — IV APAP versus Oral APAP.
Summary of Findings by Comparison — IV APAP Versus IV NSAIDs.
Summary of Findings by Comparison — IV APAP Versus IV Opioids.
Summary of Findings by Comparison — IV APAP Versus Placebo.
Summary of Recommendations in the Included Guideline.
Note that this appendix has not been copy-edited.
Overlap in Relevant Primary Studies Between Included Systematic Reviews.
Note that this appendix has not been copy-edited.
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