Acetaminophen, better known by its brand name Tylenol®, is widely used in the inpatient and outpatient settings for pain management and fever relief. It is favorable in many populations because of its opioid sparing properties and relatively favorable side effect profile. Acetaminophen is most commonly used in oral formulations including tablets, capsules and oral solutions, and also is available as a suppository. In 2010, intravenous acetaminophen, also known as Ofirmev®, was approved by the FDA. However, the place in therapy of intravenous acetaminophen has not yet been well established.

The FDA-approved uses of intravenous acetaminophen include management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever, which are identical to that of oral acetaminophen.1,2 The mechanism of action of acetaminophen has not exactly been identified, but is known to inhibit cyclooxygenase (COX) pathways.3 The adverse effects of acetaminophen include nausea, vomiting, headache and insomnia. Among its side effects, the most serious is risk for hepatic injury, which may be reduced in IV administration due to avoidance of first-pass hepatic exposure.1,2 Acetaminophen is contraindicated in patients with severe hepatic impairment or liver disease due to the risk of hepatotoxicity.1,2 The dosing is typically weight-based for children, but for adults, there is a more standardized dosing regimen. Oral Tylenol® is available in regular strength 325 mg tablets, 500 mg extra strength tablets, and 650 mg extended-release tablets. In pediatrics, it is recommended not to exceed five doses in 24 hours regardless of weight. For adult patients, the maximum daily recommended dose is 3000 mg, though this was lowered from 4000 mg per day to encourage safer use of acetaminophen and reduce risk of hepatotoxicity.1

In terms of pharmacokinetics, the main differences between oral and intravenous acetaminophen are the time of onset and duration of action. Oral acetaminophen has an onset of action of less than an hour, but intravenous acetaminophen has an onset of five to 10 minutes. In addition, oral acetaminophen has a duration of action of four to six hours, whereas intravenous acetaminophen has a duration exceeding six hours.4 Intravenous acetaminophen also has more predictable pharmacokinetic and pharmacodynamic properties due to the formulation itself. Van der Westhuizen, et al., found that 96% of patients receiving intravenous acetaminophen reached target concentration, whereas only 67% in the oral group reached target concentration.5 More reliable absorption rates are a possible advantage compared to oral preparations.

Though these pharmacokinetic properties may make intravenous acetaminophen appear more favorable, it has several disadvantages. Intravenous acetaminophen is much more costly than oral acetaminophen. The average cost of a dose of intravenous acetaminophen is $29.26, which is considerably more expensive than the average cost of $0.04 for an oral tablet dose.4 Additionally, it must be infused over 15 minutes which may be inconvenient for some patients.2 When reconstituted, intravenous acetaminophen is prepared as 1000 mg in 100 mL of solution, which should be considered in patients who require fluid restriction, as this may be an issue. Acetaminophen for injection also is packaged in a glass vial, which is not ideal for storage purposes and can lead to increased wasting since each vial must be used within six hours of opening.6

Many studies have been performed to assess the differences between oral and intravenous acetaminophen, but mixed evidence has been reported. A systematic review by Jibil and others comparing the literature of analgesic efficacy, safety and pharmacokinetics between intravenous and oral acetaminophen identified no clear indication for intravenous over oral dosage forms in the majority of patients.7 Six randomized studies met inclusion criteria for this study with data on comparison of outcomes between patients receiving intravenous acetaminophen and patients receiving oral acetaminophen. Of the studies reviewed, efficacy, safety and pharmacokinetic outcomes between intravenous and oral acetaminophen were analyzed. Pettersson, et al., which was included in this study, found that the use of opioids was lower in patients receiving intravenous acetaminophen compared to the group receiving oral therapy in the post-operative setting. However, they did not report any differences in postoperative nausea and vomiting or difference in pain scores. This was likely due to the quicker onset of action of the intravenous formulation.7,8 In studies analyzing pharmacokinetic outcomes, Van der Westhuizen, et al., for example, found no evidence suggesting intravenous acetaminophen is superior to oral administration.5 The statistically significant findings of the article were not considered clinically significant and would not change current practices.  However, this study did suggest intravenous acetaminophen may have a place in therapy for patients who cannot take oral formulations and concurrently require an adjunctive agent for pain control to avoid the use of opioids. In consideration of the findings of these studies, this systematic review concluded that intravenous formulations of acetaminophen are not needed, except, perhaps, for patients without a functional gastrointestinal tract.7

In terms of more population-specific acetaminophen use, oral versus intravenous acetaminophen use has been analyzed in several studies focusing on patients receiving total joint arthroplasties. Brett and others, for example, found oral acetaminophen to be non-inferior to IV acetaminophen.9 This study compared postoperative pain scores, length of stay in recovery, and opioid-sparing effects of oral and intravenous acetaminophen in patients who had undergone knee arthroplasty. Among the results of the study, there was one significant difference in visual analog scale (VAS) pain scores in favor of intravenous acetaminophen over oral (p = 0.025) at 50 minutes after arrival in recovery.9 This significant finding can likely be attributed to the quicker onset of action of intravenous acetaminophen. In a similar study, Fillingham, et al., performed a systematic review of the use of intravenous acetaminophen in patients following total joint arthoplasty.10 This study reviewed a total of 17 publications, including five randomized clinical trials analyzing these outcomes in patients receiving intravenous and oral acetaminophen, none of which reported significant differences in postoperative pain or opioid consumption between the two dosage forms. Additionally, no post-operative complications were observed across these studies. Consequently, this study concluded that there is an absence of evidence favoring intravenous acetaminophen use. The author also noted the concern for cost, and that further studies are warranted to determine differences in efficacy between oral and intravenous acetaminophen.

Another study performed by Politi, et al., also analyzed intravenous acetaminophen use in total joint arthroplasty and found similar outcomes.11 In this prospective study, the average VAS used to assess pain was more statistically favorable in the intravenous acetaminophen group, but only in the zero- to four-hour post-operative interval. Otherwise, there were no differences between the groups. Though there was a significant difference in pain with intravenous acetaminophen in this initial time window after operative procedures, this is not regarded as clinically significant. Thus, this study determined similar outcomes to the aforementioned studies, and suggested using oral acetaminophen over intravenous acetaminophen as an adjunct to a multimodal pain regimen.

As determined from these large-scale studies and others, the place in therapy of intravenous acetaminophen remains unclear. However, intravenous acetaminophen may have a role as an adjunct agent in patients requiring pain control when opioids are to be avoided. Due to the nature of its formulation, it has a much quicker onset of action compared to the oral products, which make it seem like a desirable additional agent for multimodal pain control. Despite these benefits, there is a paucity of evidence recommending the use of intravenous acetaminophen when directly compared with oral acetaminophen, with the exception of patients who are unable to use their gastrointestinal tract. Additionally, the increased cost of intravenous acetaminophen alone is a deterrent of many hospitals including the drug in their formularies. No significant study findings have been suggestive of using intravenous acetaminophen over oral formulations in the studied patient populations. Thus, the differences between the formulations in pharmacokinetics and pharmacodynamics are likely insignificant in terms clinical applicability. Further studies could help in formulating a clearer conclusion and role in therapy, but at this time, there is no compelling indication for the use of intravenous acetaminophen.

However, the drug manufacturing company Perrigo has been granted rights to market a generic intravenous acetaminophen product starting in December 2020 by Cadence, the manufacturer of Ofirmev®. Pending the emergence of this generic formulation, there is great potential for increased utilization of intravenous acetaminophen. Though there is no overwhelming evidence supporting the use of intravenous acetaminophen over oral, hospitals may be more inclined to add this to formulary if it is less costly. Still, the place in therapy of intravenous acetaminophen would not be well established and it may only offer an alternative to opioids in patients requiring pain control who are unable to receive enteral therapy.

References

  1. TYLENOL for Healthcare Professionals. TYLENOL Professional. https://www.tylenolprofessional.com/adult-dosage. 2020
  2. Ofirmev. Package Insert. Cadence Pharmaceuticals; 2010
  3. Gerriets V, Anderson J, Nappe TM. Acetaminophen. In: StatPearls. StatPearls Publishing; 2020.
  4. Acetaminophen. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  http://online.lexi.com.  Accessed November 2, 2020.
  5. van der Westhuizen J, Kuo PY, Reed PW, Holder K. Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia. Anaesth Intensive Care. 2011;39(2):242-246. doi:10.1177/0310057X1103900214
  6. Yeh YC, Reddy P. Clinical and economic evidence for intravenous acetaminophen. Pharmacotherapy. 2012;32(6):559-579. doi:10.1002/j.1875-9114.2011.01085.
  7. Jibril F, Sharaby S, Mohamed A, Wilby KJ. Intravenous versus Oral Acetaminophen for Pain: Systematic Review of Current Evidence to Support Clinical Decision-Making. Can J Hosp Pharm. 2015;68(3):238-247. doi:10.4212/cjhp.v68i3.1458
  8. 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(3):306-309. doi:10.1053/j.jvca.2005.03.006
  9. Brett CN, Barnett SG, Pearson J. Postoperative plasma paracetamol levels following oral or intravenous paracetamol administration: a double-blind randomised controlled trial. Anaesth Intensive Care. 2012;40(1):166-171. doi:10.1177/0310057X1204000121
  10. Fillingham YA, Hannon CP, Erens GA, et al. The Efficacy and Safety of Acetaminophen in Total Joint Arthroplasty: Systematic Review and Direct Meta-Analysis. J Arthroplasty. 2020;35(10):2715-2729. doi:10.1016/j.arth.2020.05.037
  11. Politi JR, Davis RL 2nd, Matrka AK. Randomized Prospective Trial Comparing the Use of Intravenous versus Oral Acetaminophen in Total Joint Arthroplasty. J Arthroplasty. 2017;32(4):1125-1127. doi:10.1016/j.arth.2016.10.018
Author profile
Marissa Rees, PharmD

Dr. Rees is a PGY-1 acute care pharmacy practice resident at Allegheny General Hospital. For any questions concerning this article, please contact Dr. Rees at the Allegheny Health Network, Allegheny General Hospital, Center for Pharmaceutical Care, Pittsburgh, Pa., (412) 359-3192 or marissa.rees2@ahn.org.