The Role of Intravenous Acetaminophen in Acute Pain Management

A Case-Illustrated Review

Chris Pasero, MS, RN-BC, FAAN; Daphne Stannard, PhD, RN, CCRN, CCNS, FCCM

Disclosures

Pain Manag Nurs. 2012;13(2):107-124. 

In This Article

IV Acetaminophen

Intravenous acetaminophen differs in many ways from the available IV opioids and NSAIDs. It is the only approved IV nonopioid analgesic that does not include a boxed warning on the label and that is indicated for use in pediatric patients. The drug is not associated with the increased incidence of nausea, vomiting, and respiratory depression that can occur with opioids, or the platelet dysfunction, gastritis, and renal toxicity that are sometimes associated with NSAIDs (Haas, 2002; Silvanto, Munsterhjelm, Savolainen, Tiainen, Niemi, Ylikorkala, … Olkkola, 2007).

Intravenous acetaminophen has a faster onset and results in more predictable pharmacokinetics than oral or rectal acetaminophen formulations (Bertolini et al., 2006, Malaise et al., 2007). In a recent study, in which six adult volunteers were given IV, oral, or rectal acetaminophen, the mean IV Cmax (maximum plasma concentration of drug) was nearly twice that observed with oral administration and nearly four times that observed with rectal administration (Singla, Parulan, Samson, Hutchinson, Bushnell, Beja, & Royal, 2011). The IV group showed consistently earlier and higher peak plasma and cerebrospinal fluid (CSF) maximum concentration values than after either oral or rectal delivery. The variability in plasma and CSF results was much higher in the oral and rectal groups than in the group that received IV acetaminophen.

A major benefit is that IV acetaminophen may be administered before or during surgery, permitting the initiation of effective analgesic therapy in the early phase of the postoperative period (Dahl & Møiniche, 2004; Ong, Lirk, Seymour, & Jenkins, 2005). When patients are able to tolerate oral intake, they may be switched from IV to oral acetaminophen to maintain the predictable analgesia established by the IV route (Pergolizzi, Raffa, Tallarida, Taylor, & Labhsetwar, 2011).

Intravenous acetaminophen appears to avoid first-pass hepatic exposure and metabolism via portal circulation, which may reduce the potential for hepatic injury (Jahr & Lee, 2010). With therapeutic dosing (up to 4,000 mg daily) (Gregoire, Hovsepian, Gualano, Evene, Dufour, & Gendron, 2007), IV acetaminophen is rarely associated with hepatotoxicity, and it has been shown to be safe for use in some patients with underlying liver conditions (Benson, Koff, & Tolman, 2005; Rumack, 2002). Nonetheless, according to its prescribing information, IV acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease (Cadence, 2010).

Because of its efficacy, safety, lack of clinically significant drug interactions, and lack of the adverse effects associated with other analgesics, IV acetaminophen is an attractive component of a multimodal analgesic treatment plan (Groudine & Fossum, 2011).

Clinical Pharmacology

Mechanism of Action. Acetaminophen has both analgesic and antipyretic effects. Although the exact mechanisms of action of acetaminophen are still unclear, it is thought to exert its analgesic activity by inhibiting the synthesis of prostaglandins in the CNS (central acting) and peripherally blocking pain impulse generation (Aronoff, Oates, & Boutaud, 2006; Graham & Scott, 2005). Unlike NSAIDs, acetaminophen is not a peripheral COX inhibitor (Aronoff et al., 2006, Groudine & Fossum, 2011). In addition, it has been proposed that acetaminophen has a serotonergic (5-HT) mechanism and a cannabinoid agonism mechanism, which may contribute to its analgesic effect (Smith, 2009). The antipyretic effect of acetaminophen is thought to involve inhibition of the hypothalamic heat-regulating center, prostaglandin inhibition, and cannabinoid agonism (Malaise et al., 2007). The differences in mechanisms of action between acetaminophen and NSAIDs are likely responsible not only for the synergistic effect they have when used in combination, but also for the differences in safety profiles observed with the drugs (Groudine & Fossum, 2011).

Pharmacokinetics and Pharmacodynamics. The pharmacokinetics of IV acetaminophen has been studied in patients and healthy volunteers in a wide range of ages, from premature neonates to adults 60 years old (Cadence, 2010). IV acetaminophen achieves a higher Cmax and an earlier time to maximum concentration (Tmax), with less intrasubject variability than bioequivalent oral or rectal formulations (Bertolini et al., 2006; Malaise et al., 2007; Holmér Pettersson, Owall, & Jakobsson, 2004). A major advantage of IV acetaminophen is that the median time to reach Tmax for IV acetaminophen is much faster than typically reported for oral or rectal formulations (>45 minutes) (Bertolini et al., 2006). Cmax, which occurs at the end of the 15-minute infusion of IV acetaminophen, is up to 70% higher than that observed with the same dose of oral acetaminophen, although the overall exposure (area under the concentration time curve) is very similar (Cadence, 2010). The higher Cmax with IV acetaminophen compared with oral acetaminophen does not seem to compromise the drug's safety profile, because the Cmax at this dose remains far below the 150 mg/L concentration considered to be the threshold for potential hepatotoxicity (Gregoire et al., 2007).

Acetaminophen is detectable in the CSF within minutes after IV administration (Jahr & Lee, 2010; Kumpulainen, Kokki, Halonen, Heikkinen, Savolainen, & Laisalmi, 2007). The rapid CSF penetration and earlier and higher Cmax observed with IV acetaminophen seem to be responsible for its more rapid onset and peak efficacy compared with oral or rectal acetaminophen (Jahr & Lee, 2010). The drug's duration of effect is predictable, from 4 to 6 hours (Moller, Juhl, Payen-Champenois, & Skoglund, 2005).

Metabolism. Acetaminophen undergoes metabolism by the liver via three pathways: 1) conjugation with glucuronide; 2) conjugation with sulfate; and 3) oxidation via the cytochrome P450 enzyme pathway (primarily CYP2E1) (Bertolini et al., 2006; Cadence, 2010; Gelotte, Auiler, Lynch, Temple, & Slattery, 2007; Manyike, Kharasch, Kalhorn, & Slattery, 2000).

When delivered orally, acetaminophen undergoes first-pass metabolism in the liver; however, IV administration bypasses first-pass liver metabolism (Jahr & Lee, 2010). Compared with the oral route, the IV route of administration reduces initial hepatic acetaminophen exposure by approximately twofold (Jahr & Lee, 2010).

Dosing and Administration

Intravenous acetaminophen may be given as a single dose or as repeated doses. The maximum daily dose of acetaminophen is based on all routes of administration (i.e., IV, oral, and rectal) and all products (prescription and nonprescription) containing acetaminophen. The recommended dosing for IV acetaminophen is presented in Table 2 (Cadence, 2010). It is not necessary to adjust the dose when converting between oral and IV acetaminophen in adults and adolescents (Cadence, 2010).

Intravenous acetaminophen is supplied in a 100-mL glass vial containing 1,000 mg (10 mg/mL) ready-to-use acetaminophen (i.e., no reconstitution or dilution is required) (Cadence, 2010). The entire dose of IV acetaminophen is administered over 15 minutes, and the infusion must be vented for proper delivery.

Patients who weigh <50 kg should not receive the entire 100-mL vial of IV acetaminophen. Therefore, to avoid the inadvertent delivery of the total volume of the vial to these patients, the appropriate dose must be aseptically withdrawn and placed into a separate empty sterile container (e.g., glass bottle, plastic IV container, or syringe) before administration.

Once the vacuum seal of the glass vial has been penetrated, the dose of IV acetaminophen must be administered within 6 hours. IV acetaminophen is a single-use vial, and the unused portion must be discarded (Cadence, 2010).

Other medications should not be added to the IV acetaminophen solution. Diazepam and chlorpromazine hydrochloride are physically incompatible with IV acetaminophen, so simultaneous IV administration of these drugs should be avoided (Cadence, 2010). To prevent the possibility of an air embolism, it is important to observe the end of the infusion (Cadence, 2010).

Clinical Research on the Use of IV Acetaminophen

Preemptive Analgesia. An IV formulation of acetaminophen may have important implications for implementation of a preemptive approach to the management of postoperative pain (i.e., dosing an analgesic before a pain stimulus, such as a surgical incision, with the intent to reduce subsequent pain), a concept introduced in the clinical setting decades ago (Dahl & Kehlet, 1993; Woolf & Chong, 1993). One goal of preemptive analgesia is to decrease pain by timing the analgesic's peak pharmacodynamic effect with the anticipated onset of pain or peak pain response (Dahl & Moiniche, 2004).

Two studies demonstrated a preemptive effect with the administration of IV acetaminophen before surgical incision (Arici, Gurbet, Türker, Yavaşcaoğlu, & Sahin, 2009; Prasanna & Sharma, 2010). In one of these studies (Arici et al., 2009), 82 patients undergoing total abdominal hysterectomy were randomized to receive either 1,000 mg IV acetaminophen preemptively 30 minutes before anesthesia induction (group 1; n = 28), 1,000 mg IV acetaminophen at the end of surgery before skin closure (group 2; n = 27), or placebo (group 3; n = 27). No statistically significant differences were found between the operation times among the three groups (group 1, 121.6 min; group 2, 114.3 min; group 3, 118.3 min). Postoperatively, all patients received IV PCA morphine rescue as needed. Total morphine consumption in both IV acetaminophen groups (group 1, 25.93 mg; group 2, 35.73 mg; p < .05 for both) was significantly lower than in the placebo group (62.93 mg), and the preinduction acetaminophen group used less morphine than the end-of-surgery acetaminophen group (p < .05). Another important finding was that, compared with both IV acetaminophen groups, the placebo group had a statistically significantly higher incidence of postoperative nausea, vomiting, and itching (p < .05 for each). Patients in group 1 experienced the lowest incidences of all of these adverse effects and the shortest length of hospital stay (group 1, 5.03 days; group 2, 5.20 days; group 3, 6.43 days).

In the second study of preemptive analgesia (Prasanna & Sharma, 2010), 80 patients undergoing cesarean section were randomized to receive either 1,000 mg IV acetaminophen plus 75 mg intramuscular (IM) diclofenac preemptively before surgical incision but after induction of anesthesia (n = 40) or 1,000 mg IV acetaminophen plus 75 mg IM diclofenac at the end of surgery before skin closure (n = 40). The exact time of analgesic administration was not reported, although the authors mentioned consideration of a 45-minute peak time for IM diclofenac. All patients were given 3 μg/kg IV fentanyl immediately after delivery, and postoperatively, all patients could receive as-needed rescue opioid analgesia (opioid was not named in the report). The need for rescue analgesia for treatment of breakthrough pain was recorded during cleaning after surgery, transfer from the operating room table to the stretcher, and during transport from the operating room to the PACU. Patients in the group receiving the study treatment before surgery reported significantly fewer total instances of breakthrough pain compared with patients in the group receiving study treatment at the end of surgery (45 vs. 90; p < .001). In the group receiving study treatment before surgery, seven patients required rescue opioid before transfer to the PACU and 14 patients required rescue opioid during transfer. In the group receiving study treatment at the end of surgery, 14 patients required rescue opioid before transfer to the PACU and the balance of patients (26) required rescue opioid immediately in the PACU. No other patient outcomes were reported.

Intravenous acetaminophen has been given prophylactically as a component of multimodal treatment plans for patients undergoing fast-track surgical procedures. A randomized controlled trial of 160 patients who underwent laparascopic cholecystectomy found that those who received IV acetaminophen during surgery and oral acetaminophen after surgery experienced similar pain relief and adverse effects but required less rescue medication on the first postoperative day compared with those who were given an IV COX-2–selective NSAID (parecoxib, not available in the U.S.) during surgery and an oral COX-2–selective NSAID (valdecoxib) after surgery (Tiippana, Bachman, Kalso, & Pere, 2008). A report of 500 consecutive patients who were given IV acetaminophen, parecoxib, and bupivacaine surgical site infiltration before fast-track bariatric surgery described a significant reduction in hospital stay from 3 to 2 days (Bergland, Gislason, & Raeder, 2008).

Acute Postoperative Pain in Adults. The efficacy of IV acetaminophen for the management of postoperative pain in adult patients has been studied in several randomized placebo-controlled trials around the world demonstrating effective pain relief and opioid dose–sparing effects (Table 3) (Atef & Fawaz, 2008; Juhl, Norholt, Tonnesen, Hiesse-Provost, & Jensen, 2006; Memis, Inal, Kavalci, Sezer, & Sut, 2010; Moller et al., 2005; Sinatra, Jahr, Reynolds, Viscusi, Groudine, & Payen-Champenois, 2005; Wininger, Miller, Minkowitz, Royal, Ang, Breitmeyer, & Singla,). Macario and Royal (2011) conducted a systematic literature review of 16 prospective randomized-controlled trials (1,464 patients, with 780 receiving IV acetaminophen) that compared IV acetaminophen with either placebo or an active comparator in patients undergoing a wide variety of surgical procedures. The active comparators in these studies were parecoxib, IV metamizol (an NSAID removed from the U.S. market in the 1970s because of its adverse effect profile), and oral ibuprofen. In seven of the eight active-comparator studies, patients receiving IV acetaminophen experienced similar pain relief as those who received the comparative agent. Of these eight, three reported significant reductions in opioid consumption, fewer patients requiring rescue analgesia, or longer time to request for rescue analgesia. In 12 of the 14 placebo-controlled trials, patients who were given IV acetaminophen experienced improved pain relief. In 10 of the 14 trials, the IV acetaminophen group had reduced opioid consumption, the duration of analgesia was longer, and fewer patients required rescue analgesics.

Total Hip or Knee Arthroplasty. Sinatra et al. (2005, 2011) reported the results of a randomized double-blind placebo-controlled clinical trial that evaluated the analgesic efficacy of single and repeated doses (every 6 hours) of 1,000 mg IV acetaminophen plus PCA morphine versus placebo plus PCA morphine for 24 hours in 101 patients with moderate to severe pain after total hip or knee arthroplasty. Treatment was initiated the morning after surgery. The primary end point of this study was pain relief measured on a 4-point scale (0 = no pain; 1 = mild pain; 2 = moderate pain; 3 = severe pain) over 6 hours. Patients who received IV acetaminophen experienced better pain relief and significant reductions in morphine consumption (46% reduction over 6 hours and 33% reduction over 24 hours) compared with those who received placebo. Furthermore, a significant improvement in median time to first rescue medication was seen with IV acetaminophen (3 hours) compared with placebo (0.8 hours). Other important findings were that adverse effects were similar between the patients treated with IV acetaminophen and those receiving placebo, and that patients' global evaluations of satisfaction with study treatment at 24 hours were significantly higher among those treated with IV acetaminophen: 79.6% of patients in the IV acetaminophen group rated their satisfaction as fair to excellent, compared with 65.4% of those in the placebo group.

Abdominal Laparoscopic Surgery. Wininger et al. (2010) reported the results of a randomized double-blind placebo-controlled clinical trial evaluating the analgesic efficacy of repeated doses of two dosing regimens of IV acetaminophen (1,000 mg every 6 hours or 650 mg every 4 hours for 24 hours) versus placebo in 244 patients with moderate to severe postoperative pain after abdominal laparoscopic surgery (included hysterectomy, cholecystectomy, and hernia repair). Patients in both IV acetaminophen dosing groups experienced statistically significantly greater pain relief over 24 hours compared with placebo.

Major Abdominal or Pelvic Surgery. Memis et al. (2010) assessed the effect of adding IV acetaminophen to IV meperidine in 40 adults admitted to the intensive care unit after major surgery. Patients were randomized to receive either 1,000 mg IV acetaminophen every 6 hours and IV meperidine as needed or placebo (IV saline) every 6 hours plus IV meperidine as needed for 24 hours. While patients were sedated and mechanically ventilated, rescue IV meperidine was administered for analgesia when Behavior Pain Scale (BPS) scores (3 = no pain; 12 = maximum pain) were >4. After extubation, rescue IV meperidine was administered when visual analog scale (VAS) scores (0 = no pain; 10 = worst pain imaginable) were >4. In the group that received IV acetaminophen, BPS and VAS scores were significantly lower (p < .01), postoperative meperidine consumption was significantly less (p < .05), the time to extubation was ~3 hours shorter, and postoperative nausea and vomiting, as well as sedation scores, were significantly lower than in the group that did not receive IV acetaminophen.

Tonsillectomy. A prospective placebo-controlled study randomized 76 adult patients undergoing tonsillectomy under general anesthesia to receive either 1,000 mg IV acetaminophen or placebo at 6, 12, and 18 hours after surgery (Atef & Fawaz 2008). Patients who reported moderate to severe pain (i.e., VAS pain score >30 mm at rest) were given IM meperidine. During the first 24 hours after surgery, meperidine consumption was significantly lower among the patients who received IV acetaminophen (18 mg) than those who received placebo (82 mg). Patients in the IV acetaminophen group reported significantly less pain than those in the placebo group. Insufficient pain relief (defined as a VAS score of >30 mm at rest and >50 mm on swallowing) occurred more often in patients in the placebo group than in the IV acetaminophen group (p < .001). In this study, no significant difference in adverse effects was seen between the two groups.

Dental Surgery. Two randomized double-blind studies evaluated the efficacy of a single dose of IV acetaminophen versus placebo in adults with moderate to severe pain after third molar extraction. Moller et al. (2005) compared the efficacy of IV infusions of 1,000 mg acetaminophen (n = 51) and placebo (n = 50) for 6 hours after starting the 15-minute infusions and found that IV acetaminophen provided significantly more effective pain relief than placebo (p < .01), with a significantly longer duration of analgesia and better scores on patients' global evaluation compared with placebo. Juhl et al. (2006) conducted a similar study (n = 297); however, they included a 2,000-mg IV acetaminophen group and evaluated efficacy over 8 hours. They found that pain relief and duration of analgesia with the 2,000 mg dose were significantly superior compared with either the recommended 1,000 mg dose or placebo, with no difference in adverse effects among the groups.

Peri- and Postoperative Pain in Pediatric Patients. The efficacy of 15 mg/kg IV acetaminophen for the management of perioperative pain in pediatric patients has been studied in several randomized active comparator–controlled trials (Table 4) (Alhashemi & Daghistani, 2006, 2007; Capici, Ingelmo, Davidson, Sacchi, Milan, Sperti, … Fumagalli, 2008; Murat, Baujard, Foussat, Guyot, Petel, Rod, & Ricard, 2005). Murat et al. (2005) conducted a randomized, active-controlled, double-blind, parallel-group, multicenter study in 183 children ranging in age from 1 to 12 years. Patients were randomized to receive either a single dose of IV acetaminophen (15 mg/kg) or a bioequivalent dose of IV propacetamol (the prodrug of acetaminophen, not available in the U.S.; 30 mg/kg) when their postoperative pain intensity, as rated by the investigator, was >30 on a 0–100-mm VAS. Both treatments rapidly reduced pain scores, with a steep reduction from baseline pain intensity during the first 15-minute interval after infusion. The duration of analgesia, measured as the time to first rescue dose, was >4 hours for both groups. Similarly, only ~20% of the patients in both groups required rescue medication, and global evaluations of "excellent" were reported for 76% of patients receiving IV acetaminophen.

Alhashemi and Daghistani (2006) conducted a randomized double-blind study comparing the analgesic effects of intraoperative IV acetaminophen (15 mg/kg) and IM meperidine (1 mg/kg) in 80 pediatric patients (3–16 years old) undergoing tonsillectomy. Patients who received IV acetaminophen experienced pain relief similar to those who received IM meperidine; however, those who received IV acetaminophen experienced less sedation in the early recovery period and were ready for discharge from the recovery room earlier than those who had received meperidine. These same researchers conducted another study comparing intraoperative IV acetaminophen (15 mg/kg) and IM meperidine (1 mg/kg) in 40 pediatric patients (3–16 years old) undergoing dental restoration under general anesthesia (Alhashemi & Daghistani, 2007). All patients received 0.5 mg/kg oral midazolam 30 minutes before surgery and 1 μg/kg IV fentanyl immediately after induction. Anesthesia was induced with either sevoflurane inhalation or 2–3 mg/kg IV propofol and was maintained with sevoflurane. Patients who received IV acetaminophen had slightly higher pain scores but were ready for discharge from the recovery room earlier than those who received meperidine.

In a study of 46 pediatric patients (2–5 years old) who underwent adenotonsillectomy, patients were randomized to receive either rectal acetaminophen (40 mg/kg) or IV acetaminophen (15 mg/kg) after induction of anesthesia (Capici et al., 2008). Patients received a standardized anesthetic, which included 2 μg/kg fentanyl, and rescue analgesia (IV fentanyl) was provided after surgery if pain scale scores were ≥4. Ninety-eight percent (45/46) of the children required rescue analgesia, mostly 6–10 hours after surgery. In this study, the time to first rescue analgesia was significantly longer among the children receiving rectal acetaminophen (median 10 hours) than in the group receiving IV acetaminophen (median 7 hours; p = .01).

Safety Profile

Intravenous acetaminophen has been well tolerated in 1,375 patients (1,020 adults and 355 pediatric patients) in clinical trials, establishing an impressive safety profile (Atef & Fawaz, 2008; Cadence, 2010; Memis et al., 2010; Sinatra et al., 2005, 2011; Wininger et al., 2010). Furthermore, the safety of IV acetaminophen is supported by more than 8 years of clinical postmarketing safety experience outside the U.S., as well as more than 60 years of clinical experience with oral and rectal formulations (Wininger et al., 2010).

Adult Patients. In clinical trials, 1,020 adult patients were treated with IV acetaminophen; 380 of these (37%) received at least five doses and 173 (17%) received more than ten doses. Eighty-seven percent (n = 886) of the patients received 1,000 mg IV acetaminophen every 6 hours; the remaining 134 patients were treated with 650 mg IV acetaminophen every 4 hours (Cadence, 2010). Fifteen percent of the patients treated with IV acetaminophen in clinical studies were ≥65 years old, and 5% were ≥75 years old. No overall differences in safety were observed between older and younger patients (Cadence, 2010).

The primary safety concern with acetaminophen is its potential hepatic toxicity when used at doses higher than recommended (>4,000 mg/d for adult patients) (U.S. Food and Drug Administration, 2009). According to postmarketing surveillance, hepatic toxicity associated with acetaminophen is rare—occurring in fewer than 1 in 500,000 treated patients (Sinatra et al., 2005). In a pooled analysis of eight multicenter, double-blind, randomized, placebo-controlled studies (four single-dose and four multiple-dose studies; n = 1,064) conducted in the U.S. to evaluate the hepatic safety of IV acetaminophen versus placebo, liver enzyme elevations in patients treated with IV acetaminophen were similar to those who received placebo. In one of the trials, in which patients received repeated doses over 48 hours, the placebo group demonstrated 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 adverse effects (26/415; 6.3%) than the IV acetaminophen group (20/649; 3.1%) (Singla, Viscusi, Candiotti, Royal, & Breitmeyer, 2008).

Nonetheless, administration of acetaminophen by any route in doses higher than recommended may result in liver injury, including the risk of severe hepatotoxicity and death. Acetaminophen is found in more than 600 different prescription and over-the-counter medicines, including not only analgesics and antipyretics, but also sleep aids and cough, cold, and allergy medications. To reduce the risk of severe liver injury from acetaminophen overdosing, the Acetaminophen Awareness Coalition created the Know Your Dose (www.knowyourdose.org) patient education campaign (Acetaminophen Awareness Coalition, 2011). In addition, in January 2011, the FDA asked manufacturers of prescription acetaminophen combination products to limit the maximum amount of acetaminophen in these products to 325 mg per dosage unit (e.g., tablet, capsule) (U.S. Food and Drug Administration, 2011).

Caution must be used when administering acetaminophen to patients with liver dysfunction or active liver disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe kidney dysfunction (i.e., creatinine clearance ≤30 mL/min) (Cadence, 2010). IV acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease.

Treatment-related adverse reactions occurring in ≥3% of patients treated with IV acetaminophen in clinical trials are presented in Table 5. The most common adverse reactions in adult patients treated with IV acetaminophen are nausea, vomiting, headache, and insomnia. The pyrexia adverse reaction frequency data are included in Table 5 to point out that the antipyretic effects of IV acetaminophen may mask fever (Cadence, 2010).

When dosed appropriately, IV acetaminophen is not associated with cardiovascular thrombotic events, cognitive impairment, platelet inhibition, postoperative ileus, renal toxicity, respiratory depression, sedation, surgical site bleeding, or upper GI bleeding. Single doses of IV acetaminophen up to 3,000 mg and repeated doses of 1,000 mg every 6 hours for 48 hours have not been shown to significantly affect platelet aggregation (Cadence, 2010). No immediate or delayed effects on small vessel hemostasis have been seen. In clinical studies in which healthy volunteers as well as patients with hemophilia received multiple doses of oral acetaminophen, no significant changes in bleeding time were observed (Cadence, 2010). Although no studies have been conducted on short-term use, long-term use of acetaminophen at maximum dose has been shown to increase international normalized ratio (INR) in individuals stabilized on sodium warfarin (Coumadin); therefore, monitoring INR in such patients after surgery is recommended (Pasero, Portenoy, & McCaffery, 2011).

Pediatric Patients. Intravenous acetaminophen is the only IV agent approved to treat both pain and fever in pediatric patients aged ≥2 years. The effectiveness of IV acetaminophen for the treatment of acute pain and fever has not been studied in pediatric patients <2 years old (Cadence, 2010). The most common adverse events reported in pediatric patients treated with IV acetaminophen are nausea, vomiting, constipation, pruritus, agitation, and atelectasis (Cadence, 2010).

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