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Intravenous Acetaminophen

A versatile resource for acute pain management

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Intravenous (IV) acetaminophen is a versatile resource that can improve the management of acute pain. The Food and Drug
Administration granted approval for the use of IV acetaminophen (Ofirmev) in November 2010. It is indicated for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever in patients 2 years and older.1 Prior to this approval, acetaminophen was only available in oral and rectal suppository formulations in the United States. In many other countries, IV acetaminophen has been available since 2001.

 

Analgesic Regimen

In 1986, the World Health Organization (WHO) established analgesic treatment guidelines describing a three-step ladder for cancer pain.2 Similar to this analgesic ladder, a stepwise multimodal pain therapy ladder has been proposed for the management of postoperative pain (Table 1).3

Combining agents with different mechanisms of action may have a synergistic effect and allow for the use of lower doses than with monotherapy. This means that a multimodal pain management plan can improve pain relief, reduce opioid consumption and minimize opioid-related adverse effects (AEs).4-9 Studies have shown that treatment with IV acetaminophen reduced opioid consumption in a variety of surgeries. For example, in a study of patients with moderate to severe pain after total hip or knee replacement, patients treated with IV acetaminophen consumed 46% less morphine over 6 hours and 33% less morphine over 24 hours than those who received placebo.10 In a study of patients who had undergone major abdominal or pelvic surgery, postoperative opioid consumption was 77 mg among the patients who received IV acetaminophen and 198 mg among those who received placebo (P <.01).11 In a study of adults who had undergone outpatient tonsillectomies, postoperative opioid consumption was 18 mg among the patients treated with IV acetaminophen and 82 mg among those who had received placebo (P <.001).12

In addition to its opioid-sparing potential, the IV formulation of acetaminophen is particularly useful in a number of situations that occur in the hospital setting (Table 2).

 

Advantages

IV acetaminophen is superior to oral or rectal acetaminophen for a number of reasons. IV administration of analgesics is the preferred route in the perioperative period, especially in situations when a patient is unable to take medications by mouth.6,7 IV acetaminophen has a faster onset of action and results in more predictable pharmacokinetics than oral or rectal acetaminophen formulations.13 IV acetaminophen demonstrates earlier and greater cerebrospinal fluid penetration as a result of the earlier and higher plasma peak with IV administration compared with oral or rectal forms.13

After oral administration, acetaminophen is quickly absorbed from the gastrointestinal tract into the bloodstream and undergoes first-pass metabolism by the liver. IV acetaminophen appears to avoid first-pass hepatic metabolism, which reduces hepatic exposure and may reduce the potential for hepatic injury, especially in patients older than 65, patients with liver disease, and patients who take concomitant hepatotoxic medications or consume large amounts of alcohol.14

 

Pharmacodynamics

IV acetaminophen displays a rapid onset of action within 15 minutes of administration, and the peak effect occurs within 1 hour. The duration of effect is predictable, between 4 and 6 hours.15 Repeated doses of IV acetaminophen at 1,000 mg every 6 hours for 48 hours do not significantly affect platelet aggregation.1 No immediate or delayed effects on small-vessel hemostasis have been documented.1 In clinical studies of both healthy subjects and patients with hemophilia, no significant changes in bleeding time occurred after multiple doses of oral acetaminophen.1

 

Efficacy and Safety

Efficacy for Pain. The FDA approval of IV acetaminophen for the treatment of acute pain in adults was based on the results of two randomized, double-blind, placebo-controlled clinical trials in patients with postoperative pain.10,16

The first study evaluated the analgesic efficacy of repeated doses of IV acetaminophen 1,000 mg plus patient-controlled analgesia (PCA) with morphine compared with placebo plus PCA morphine every 6 hours for 24 hours in 101 patients with moderate to severe pain after total hip or knee replacement. Pain relief scores over 24 hours were statistically higher among the group that received IV acetaminophen compared to those that received placebo. In addition, IV acetaminophen significantly reduced morphine consumption vs. placebo (46% reduction over 6 hours and 33% reduction over 24 hours). However, the clinical benefit of reduced opioid consumption was not demonstrated.10

The second study evaluated the analgesic efficacy of repeated doses of IV acetaminophen 1,000 mg every 6 hours or 650 mg every 4 hours for 24 hours vs. placebo in the treatment of 244 patients with moderate to severe postoperative pain after abdominal laparoscopic surgery. Patients who received IV acetaminophen (both dosing regimens) experienced a statistically significant reduction in pain intensity over 24 hours compared to those who received placebo.16

Efficacy for Fever. The efficacy of IV acetaminophen 1,000 mg in the treatment of adult fever was evaluated in a randomized, double-blind, placebo-controlled clinical trial in 60 adult men with induced fever.17 Compared with placebo, a single dose of IV acetaminophen produced a rapid (beginning 15 minutes after infusion completion) decrease in temperature that persisted throughout the 6-hour study period. In another study of healthy adult men with induced fever, the onset of antipyretic efficacy of a single dose of IV acetaminophen 1,000 mg (n = 45) was compared with that of oral acetaminophen 1,000 mg (n = 36) over 6 hours. A single dose of IV acetaminophen was as effective in reducing fever as oral acetaminophen.18

Compared to oral acetaminophen, IV acetaminophen rapidly blunted the peak temperature after fever induction. Beginning at 30 minutes after the start of administration (15 minutes after infusion completion), statistically significant reductions in temperature were observed at every assessment time point through 90 minutes (P <.0202). The maximum mean observed temperature difference between the two groups was only 0.3°C.

Safety. AEs that occurred in at least 3% of patients treated with IV acetaminophen included nausea, vomiting, headache and insomnia.1 When used at recommended doses (Table 3), IV acetaminophen has not been associated with respiratory depression, sedation or cognitive impairment in older patients. In addition, IV acetaminophen has not been found to cause postoperative ileus, upper gastrointestinal or surgical site bleeding, renal toxicity, platelet aggregation inhibition, or cardiovascular thrombotic events.1

Postmarketing reports of hypersensitivity and anaphylaxis (including infrequent reports of life-threatening anaphylaxis requiring emergent medical attention) associated with the use of acetaminophen have been made. Clinical signs of these reactions included swelling of the face, mouth and throat, respiratory distress, urticaria, rash and pruritus. IV acetaminophen should be discontinued immediately if symptoms associated with allergy or hypersensitivity occurs. IV acetaminophen should not be administered to patients with acetaminophen allergy.1

Chronic oral acetaminophen use at a dose of 4,000 mg/day may cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant. No studies have been performed to evaluate the short-term use of IV acetaminophen in patients on oral anticoagulants; however, more frequent assessment of INR may be appropriate in patients who take these agents.1

Efficacy and Safety in Elderly Patients. Of the 1,020 patients in clinical studies of IV acetaminophen, 153 (15%) were at least 65 and 51 (5%) were 75 or older. No overall differences in safety or effectiveness were observed between the elder and younger patients.1

The effects of age on the pharmacokinetics of IV acetaminophen were explored in a recent study in which a single 1,000-mg dose of IV acetaminophen was given to 10 patients who underwent orthopedic procedures. The patients were separated into four cohorts according to age range: 20 to 40, 60 to 70, 70 to 80 and 80 to 90.19 Higher concentrations of acetaminophen were observed in the two older age cohorts, caused by a significantly lower clearance (P = .004) and volume of distribution (P = .007) compared to those observed in the group that was 20 to 40 years old. The standard 1,000- mg dose of IV acetaminophen resulted in 36% to 68% greater exposure (AUC) and similar values for Cmax and time to Cmax in the two older groups compared with the youngest group. No clinical signs of liver toxicity were observed.

In the pediatric population, IV acetaminophen is the only IV agent approved to treat both pain and fever in children 2 years and older. The most common AEs in children treated with IV acetaminophen are nausea, vomiting, constipation, pruritus, agitation and atelectasis.1

 

Hepatotoxicity

The main safety concern with acetaminophen is potential hepatotoxicity when used at higher-than-recommended doses (more than 4,000 mg/day for adult patients).20 However, hepatic toxicity associated with acetaminophen is rare; it occurs in less than 1 in 500,000 treated patients.10 In a pooled analysis of eight multicenter, double-blind, randomized, placebo-controlled studies (four single-dose and four multiple-dose studies; N=1064) conducted in the U.S. to evaluate the hepatic safety of IV acetaminophen vs. placebo, liver enzyme elevations in patients treated with IV acetaminophen were comparable to those in patients who received placebo. In a trial in which patients received repeated doses over 48 hours, the placebo group reported a higher rate and greater severity of liver enzyme elevations (6/165; 3.6%) than the IV acetaminophen group (3/166; 1.8%), and the placebo group had a slightly higher rate of hepatic AEs (26/415; 6.3%) than the IV acetaminophen group (20/649; 3.1%).21

IV acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease. In addition, caution must be used when administering acetaminophen to patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance 30 mL/min or less).1

 

Dosing

IV acetaminophen is administered over 15 minutes and may be given as a single or repeated dose. No dose adjustment is necessary when converting between oral and IV acetaminophen dosing in adults and adolescents. The maximum daily dose of acetaminophen is based on all routes of administration (IV, oral and rectal) and all products (prescription and nonprescription) containing acetaminophen. Monitor the end of the infusion to prevent the possibility of an air embolism.1

 

Patient Satisfaction

Another benefit of IV acetaminophen is improved patient satisfaction. In a pooled analysis of 717 patients from five randomized, controlled trials, the incidence of "excellent" patient satisfaction was 32.3% in the IV acetaminophen group compared to 15.9% in the placebo group (P <0.001). Patient satisfaction with IV acetaminophen was independent of the type of surgery, duration of anesthesia, postoperative opioid consumption and postsurgical pain.22

 

Cost

IV acetaminophen is supplied in a 100-mL glass vial containing 1,000 mg acetaminophen (10 mg/mL). Although the cost of IV acetaminophen is greater than that of oral or rectal acetaminophen, the clinician must weigh its benefits with the risk of increased overall healthcare costs due to adverse events related to increased opioid consumption for patients who cannot tolerate oral acetaminophen and refuse rectal acetaminophen. As a component of multimodal analgesia, IV acetaminophen can reduce overall healthcare costs by reducing the amount of opioids required for pain control. A number of published studies have evaluated IV acetaminophen in connection with events commonly associated with enhancing hospital operational efficiency by decreasing resource utilization.23 These events include: total hospital length of stay, time spent in the postanesthesia care unit, time to extubation in the intensive care unit, time to ambulation, and the incidence of adverse drug events such as postoperative nausea and vomiting,24 sedation and pruritus.

Editor's note: For a list of practical tips for using IV acetaminophen, see the online posting of this article.

 

Diane M. Santangelo is an adult nurse practitioner in the Department of Anesthesia/Acute Pain Service at Stony Brook University Medical Center in Stony Brook, N.Y. Jeanne Martin is an adult nurse practitionerin  the Department of Urology at Stony Brook University Medical Center. The authors have completed disclosure statements and report that they received writing support from Karen Cooksey, a freelance medical writer whose work was funded by Cadence Pharmaceuticals Inc.

 

References

1. Ofirmev (acetaminophen) injection. Package insert. San Diego, CA: Cadence Pharmaceuticals, Inc; 2010.

2. World Health Organization. WHO's pain ladder for adults. http://www.who.int/cancer/palliative/painladder/en/

3. Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. 2002;288(5):629-632.

4. 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;16(2):248-273.

5. Jarzyna D, et al. American Society for Pain Management Nursing guidelines on monitoring for opioid-induced sedation and respiratory depression. Pain Manag Nurs. 2011;12(3):118-145.

6. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21(3):185-211.

7. Malaise O, et al. Intravenous paracetamol: a review of efficacy and safety in therapeutic use. Future Neurol. 2007;2(6):673-688.

8. Oderda GM, et al. Opioid-related adverse drug events in surgical hospitalizations: impact on costs and length of stay. Ann Pharmacother. 2007;41(3):400-406.

9. Wheeler M, et al. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain. 2002;3(3):159-180.

10. Sinatra RS, et al. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology. 2005;102(4):822-831.

11. Memis D, 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(3):458-462.

12. Atef A, Fawaz AA. Intravenous paracetamol is highly effective in pain treatment after tonsillectomy in adults. Eur Arch Otorhinolaryngol. 2008;265(3):351-355.

13. Singla NK, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral or rectal acetaminophen. Pain Pract. 2012;12(7):523-532.

14. Royal MA, et al. Route of administration may significantly impact hepatic acetaminophen exposure. Abstract. ASRA Fall 2009 Annual Pain Medicine Meeting and Workshops, San Antonio, TX, November 19-22, 2009. http://www.asra.com/display_fall_2009.php?id=107

15. Moller PL, et al. Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery. Anesth Analg. 2005;101(1):90-96.

16. Wininger SJ, 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(14):2348-2369.

17. Kett DH, et al. A randomized study of the efficacy and safety of intravenous acetaminophen vs. intravenous placebo for the treatment of fever. Clin Pharmacol Ther. 2011;90(1):32-39.

18. Peacock WF, et al. A randomized study of the efficacy and safety of intravenous acetaminophen compared to oral acetaminophen for the treatment of fever. Acad Emerg Med. 2011;18(4):360-366.

19. Liukas A, et al. Pharmacokinetics of intravenous paracetamol in elderly patients. Clin Pharmacokinet. 2011;50(2):121-129.

20. U.S. Food and Drug Administration. Acetaminophen overdose and liver injury-background and options for reducing injury. http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4429b1-01-FDA.pdf

21. Singla N, et al. A review of the intravenous acetaminophen placebo-controlled clinical trial safety experience: A focus on hepatic transaminases. 33rd Annual Regional Anesthesia Meeting, A-114. http://www.asra.com/display_spring_2008.php?id=131

22. Portillo J, et al. Patient satisfaction with intravenous acetaminophen: a pooled-analysis of randomized, placebo-controlled, scheduled-dosed studies in the acute postoperative setting. Presented at: the American Society of Health-System Pharmacists, Dec. 3, 2012. Las Vegas. Poster 3-191.

23. IV acetaminophen: a review of pharmacoeconomic science for perioperative use. Amer J Ther. 2013;20(2):189-199.

24. Apfel CC, et al. Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis. Pain. 2013;154(5):677-689. 
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