Abstract

Background. Unrelieved postoperative pain may result in pain/suffering, as well as multiple physiological and psychological consequences (e.g., splinting, impaired gastrointestinal motility/ileus, and impaired wound healing) which may adversely affect perioperative outcomes and contribute to increased length of stay. Multimodal or balanced analgesia, utilizing regional analgesic techniques (where possible) and nonopioid analgesics appear to represent a viable strategy to decrease systemic opioid consumption and improve postoperative analgesia. The use of multimodal analgesic strategies may result in reduced frequency and severity of unwanted opioid-related adverse effects, better clinically meaningful pain relief, diminished opioid consumption, and an overall improvement of patient satisfaction as well as health outcomes (e.g., earlier ambulation and discharge).

Objectives. Review key aspects of intravenous (i.v.) acetaminophen (APAP) use in the postoperative setting.

Design. Focused literature review.

Results. Intravenous APAP is safe, effective for mild-to-moderate postoperative pain, well-tolerated, and has a very favorable side effect profile with no clearly demonstrated clinically significant drug–drug interactions. It does not exhibit any significant effects on platelet aggregation and therefore may be the preferred nonopioid analgesic when surgical bleeding is an issue.

Conclusion. The i.v. formulation of APAP represents a safe and effective first-line analgesic agent for the treatment of acute mild-to-moderate pain in the perioperative setting when oral agents may be impractical or when rapid onset with predictable therapeutic dosing is required.

Introduction

One of the primary goals of postoperative pain relief is to provide subjective comfort, inhibit trauma-induced afferent pain transmission, and to blunt the autonomic and somatic reflex responses to pain, leading to enhanced restoration of function and enhancing recovery of the ability to breath, cough, and ambulate without limitations. Despite our increased knowledge in the last decade of the pathophysiology and pharmacology of nociception, acute postoperative pain still remains a major problem [1]. Patients continue to report that one of their primary preoperative concerns is the severity of postoperative pain [1,2]. This appears to be justified, as it has been reported that 31% of patients suffer from severe or extreme pain and another 47% from moderate pain [1].

Unrelieved postoperative pain may result not only in suffering and discomfort, but may also lead to multiple physiological and psychological consequences, which can contribute to adverse perioperative outcomes [3]. Inadequate perioperative analgesia can potentially contribute to a higher incidence of myocardial ischemia, impaired wound healing [4,5], and delayed gastrointestinal (GI) motility resulting in prolonged postoperative ileus [6]. Furthermore, unrelieved acute pain may lead to poor respiratory effort and splinting which can result in atelectasis, hypercarbia, or hypoxemia, contributing to a higher incidence of postoperative pneumonia [3]. In addition, unrelieved perioperative pain may contribute to psychological distress, anxiety, sleeplessness and helplessness, impaired postoperative rehabilitation, and potentially long-term psychological consequences [7], as well as the possibility of chronic postsurgical pain [8–10].

Unimodal postoperative analgesic techniques cannot be expected to provide sufficient pain relief allowing normal function without the risks of adverse effects (AEs) [11,12]. The concept of multimodal analgesia was introduced more than a decade ago as a technique to improve analgesia and reduce the incidence of opioid-related adverse events [11]. The rationale for this strategy is to achieve sufficient analgesia due to the additive or synergistic effects between different analgesics. This allows for a reduction in the doses of these drugs and, thus, a lower incidence of AEs. Unfortunately, much of the existing literature in acute pain management has utilized single analgesic techniques and failed to address the issue of pain during daily function (cough, ambulation, physical therapy, etc.). In addition to a lower incidence of AEs and improved analgesia, it has been demonstrated that multimodal analgesia techniques may provide for shorter hospitalization times, improved recovery and function, and decreased health care costs following surgery [13,14]. Currently, the American Society of Anesthesiologists Task Force on Acute Pain Management [15] and the Agency for Health Care Research and Quality [16] advocates a multimodal analgesic approach for the management of acute pain. The practice guidelines for acute pain management in the perioperative setting specifically state “unless contraindicated, all patients should receive around-the-clock regimen of nonsteroidal anti-inflammatory drugs (NSAIDs), selective Cyclooxygenase-2 Inhibitors (COXIBs), or acetaminophen”[15].

Thus, postoperative pain management often includes the use of nonopioid analgesics in conjunction with opioids [17]. While these agents are typically not sufficient to treat moderate-to-severe pain by themselves, they are useful adjuncts to opioids that may result in significant reductions in opioid consumption and possible avoidance of opioid-related adverse events. NSAIDs and COXIBs have antipyretic, analgesic, and anti-inflammatory effects, while acetaminophen (APAP) has antipyretic and analgesic effects but limited peripheral anti-inflammatory activity. The use of NSAIDs is associated with an increased risk of specific adverse events, including GI bleeding, GI mucosal damage, renal impairment, and postoperative bleeding [17]. In contrast, APAP has been demonstrated to be well-tolerated [18] with minimal adverse events [19,20]. In 2008, Toms and colleagues [21] updated the original 2004 Cochrane review by Barden et al. [19], and observed that a single dose of APAP provided effective postoperative analgesia for about half of patients for about 4 hours and was associated with few, mainly mild, AEs.

The difference in safety profiles between APAP and NSAIDs is likely due to mechanistic differences in how they produce analgesia. NSAIDs primarily act through inhibition of prostaglandin (PG) synthesis [22]. This is mediated by inhibiting the function of cyclooxygenase (COX) isoenzymes. In 1971, Sir John Vane discovered the central role of COX in the mode of action of NSAIDs [23]. COX-1 is considered a “housekeeping” enzyme, as the PGs it produces help to maintain normal organ function, such as gastric mucosa protection, renal function support, and stimulation of platelet (PLT) aggregation; whereas COX-2 is expressed during inflammation and cell damage, and the PGs it produces accelerate the inflammatory process. The majority of NSAIDs act on both COX-1 and COX-2 isoforms; however, COXIBs that are selective for COX-2 are also available for oral use in the United States [24].

While APAP, NSAIDs, and COXIBs are widely used for pain relief, there are a limited number of studies comparing the efficacy of the intravenous (i.v.) formulations of these drugs. As i.v. APAP was not available when most of these studies were done and i.v. parecoxib is still not available in the United States, the published i.v. data come primarily from studies conducted at sites outside the United States, where there are also multiple commercialized i.v. NSAIDs. This paper discusses the available data evaluating the relative efficacy and safety of i.v. formulations of APAP and NSAIDs/COXIBs. Furthermore, in some instances, i.v. and oral preparations have been studied in head-to-head evaluations, despite differences in onset of efficacy and blood plasma levels. Finally, it is important to note that comparisons to established NSAIDs are most appropriately made using postsurgical pain models. Therefore, the studies discussed will be limited to these models.

The analgesic efficacy of anti-inflammatory agents and oral COX-2 inhibitors may be related in part to blood-brain barrier penetration [25]. Buvanendran and colleagues have shown that cerebrospinal fluid (CSF) rofecoxib levels are approximately15% of plasma levels and that repeated daily dosing more than doubles the area under the curve (AUC) in CSF [26]. As APAP's primary analgesic effect appears to be due to a central nervous system (CNS) site of action, the i.v. route is likely to have a significant advantage over the oral route due in the perioperative period to earlier and higher peak CSF levels.

Permeability of the blood-brain barrier to currently used NSAIDs and COXIBs may be pharmacodynamically important [27]. The main process by which a drug passes from the blood stream to the CNS is passive diffusion, for which degree of protein binding, lipophilicity, and ionization are critical determinants of transfer [28]. When peripheral inflammation is not a significant factor, agents that rapidly penetrate the blood-brain barrier may represent better analgesics, especially in the perioperative period. The COXIBs have been demonstrated to rapidly reach the CNS in humans in concentrations sufficient to inhibit central COX-2 activity [27]. The CNS penetration of NSAIDs is relatively rapid, but high protein binding may cause central analgesic efficacy to be delayed until sufficient CNS levels are achieved. Studies of CNS penetration have been performed for indomethacin [29], ibuprofen [30], and ketoprofen [31,32].

APAP

APAP, known as paracetamol outside the United States, has been available as an analgesic and antipyretic agent in the United States and the United Kingdom since the 1950s [33,34]. Since that time, it has developed an established record of tolerance, safety, and efficacy for both adults and children [17]. Currently, APAP is the most commonly prescribed analgesic and antipyretic in children [34] and is indicated for the short-term management of mild-to-moderate pain and the reduction of fever in both children and adults [17]. Intravenous APAP has been approved in approximately 80 countries in Europe, Asia-Pacific, Middle East, Africa, and other regions outside the United States primarily as Perfalgan and other trade names (Bristol-Myers Squibb Company, New York, NY, USA). Over 440 million units (1,000 mg equivalent) have been distributed since its first commercialization in Europe in 2002 through April 2010, representing over 65 million estimated patient exposures. OFIRMEV (APAP for injection; Cadence Pharmaceuticals, Inc., San Diego, CA, USA) received approval by the U.S. Food and Drug Administration (FDA) in 2010.

APAP—Mechanisms of Action

The mechanism of APAP-mediated pain relief is still not completely understood. However, it has been shown that APAP rapidly enters the intact CNS and the majority of the mechanisms involved in analgesia occur in the CNS [34,35]. APAP has been demonstrated to centrally inhibit PGs via the COX pathway [24,29,36], reinforce the descending serotonergic inhibitory pain pathways [37–39], trigger indirect activation of cannabinoid CB1 receptors [38,40], and inhibit nitric oxide pathways [41,42] through N-methyl-d-aspartate or substance P [22,43,44]. Despite the fact that APAP inhibits COX-1 and COX-2 [44], it has weak peripheral anti-inflammatory activity, limited GI effects, and a slight, clinically insignificant impact on PLT function [45]. Hinz and colleague postulated that APAP functions in part via preferential COX-2 blockade [46]. Ex vivo COX inhibition and pharmacokinetics (PKs) of APAP were assessed in five volunteers receiving single 1,000 mg doses orally. Coagulation-induced thromboxane B2 and lipopolysaccharide-induced prostaglandin E2 (PGE2) were measured ex vivo and in vitro in human whole blood as indices of COX-1 and COX-2 activity. In vitro, APAP elicited a 4.4-fold selectivity toward COX-2 inhibition (IC50 = 113.7 µmoles/L for COX-1; IC50 = 25.8 µmoles/L for COX-2 [46]). It has also been postulated that APAP is only able to inhibit COX isoforms at sites where peroxide levels are low, such as the CNS [36,47]. Therefore, at sites of high peroxide concentration, such as sites of inflammation, APAP has reduced activity against COX [34,36,47].

The introduction of an i.v. formulation of APAP has provided a convenient and fast-acting analgesic that results in rapid onset of pain relief, reduced time to meaningful pain relief, and reduced time to maximal pain relief compared to the oral formulation [17,35,48,49]. Double-blind clinical trials have shown that i.v. APAP was significantly better at providing analgesia than placebo in patients undergoing orthopedic [50] or gynecological surgery [17] and it has been demonstrated to reduce opioid requirements following surgery. Intravenous APAP 1 g every 6 hours following orthopedic surgery resulted in a 33% reduction in morphine consumption over 24 hours [50]. Intravenous APAP also reduced the need for rescue medication following tonsillectomy or endoscopic sinus surgery, with administration of i.v. APAP resulting in fewer doses of meperidine or oxycodone [51]. In the United Kingdom, i.v. APAP is currently indicated for the short-term treatment of moderate pain or fever when the rapid onset of analgesia is clinically justified (i.e., following surgery) or when oral administration is not possible for both adults and children (weighing more than 33 kg) [52].

APAP Dosing

APAP is available worldwide in rectal, oral, and i.v. formulations. Peak APAP plasma concentrations occur 3.5–4.5 hours after rectal administration, 45–60 minutes after oral administration, and at the end of the 15-minute i.v. infusion [44,49,53]. Rectal formulations have been associated with lower bioavailability and increased interpatient variability than oral formulations, with the likelihood of obtaining subtherapeutic plasma concentrations unless a loading dose is used [54–56]. While oral bioavailability is typically quite high (85–93%), early plasma concentrations are variable and concentrations may remain subtherapeutic (<10 µg/mL) in many patients for a significant period (as long as 60 to 80 minutes) [49,53]. When oral administration is not possible or rapid onset of relief is needed, i.v. administration is the method of choice [48,53]. Intravenous APAP allows for convenient administration with a rapid onset of pain relief that may be particularly useful in a postoperative setting [57].

For oral and i.v. APAP dosing, adult and adolescent patients weighing at least 50 kg may receive a dose of 1 g every 4 to 6 hours to a maximum of 4 g/day or a dose of 650 mg every 4 hours (3,900 mg/day). The minimum duration between doses is 4 hours; for those patients with severe renal impairment (creatinine clearance rates of ≤30 mL/min), the minimum duration between doses is 6 hours [17]. For adults and adolescents weighing less than 50 kg, and all children and newborns, weight-based dosing (e.g., 10 to 15 mg/kg) should be used to calculate the APAP dose.

APAP PKs

The mean Cmax is higher, and Tmax occurs sooner for i.v. APAP compared to per os (PO) at equivalent doses. However, other PK parameters, such as metabolism, distribution, and elimination, are similar, indicating that APAP disposition is unchanged by the route of administration. In a randomized, four-period, crossover study undertaken in 38 healthy male volunteers, each subject was serially assigned in random order to receive four treatment sessions with either i.v. APAP 1 g or oral APAP 1 g, dosed at q4h (to a maximum of 4,000 mg daily) or q6h over a 48-hour treatment period with each session separated by a 72-hour washout period [58]. Intravenous APAP demonstrated an approximately 75% higher mean first-dose Cmax (i.v. q4h: 26.0 ± 7.7 µg/mL; i.v. q6h: 28.4 ± 21.2 µg/mL vs oral q4h: 15.1 ± 5.4 µg/mL; oral q6h: 15.1 ± 4.4 µg/mL) and a Tmax that occurred at the end of the 15-minute i.v. infusion which was approximately 30 minutes prior to the Tmax observed for oral APAP. Distribution and mean clearance values at steady state were comparable between the two formulations. No accumulation occurred after 12 hours of repeated dosing for either formulation regardless of dosing schedule. The route of administration did not appear to have a significant impact on fractional excretion in urine of free (unconjugated) APAP or APAP metabolites.

The putative therapeutic APAP threshold concentration for analgesia and antipyresis is 10 µg/mL and 7 µg/mL, respectively [55,59]. In part, because of its negligible protein binding and relatively high lipid solubility [60], APAP penetrates readily through an intact blood-brain barrier, and APAP concentrations in the CSF appear to be linearly dose proportional with plasma levels [61]. Therefore, the analgesic profile of the drug parallels its concentration–time curve in the CSF, which is somewhat delayed but parallel to the plasma concentration–time curve [62].

Demonstrating the importance of CSF levels of APAP, Kokki and colleagues at the University of Kuopio, Finland, studied 32 children who were undergoing lower body surgery with spinal anesthesia [35]. After i.v. dosing, APAP rapidly penetrated the intact CNS with earliest detectable levels occurring at 5 minutes. The authors noted that while oral or rectal APAP is effective, i.v. APAP leads to faster onset of efficacy with analgesic action within 15 minutes and fever reduction within 30 minutes [35].

Similar to the findings of Kumpulainen et al., the onset of analgesia after i.v. APAP occured within 15 minutes when administered to adults [17,48,63]. This faster onset may confer a clinical benefit over oral dosing with an onset ranging from 0.55 to 1.4 hours [64–66]. For example, following oral surgery, i.v. APAP had a faster onset of analgesia and was more effective in reducing pain intensity in the first hour of treatment than oral APAP [49]. Similar results were observed following orthopedic surgery [67]. Additionally, Royal et al. demonstrated faster onset of antipyresis with i.v. vs oral APAP in a fever trial [68]. Therefore, in clinical situations where rapid onset of action is desired or where the patient is unable to reliably tolerate oral intake, an i.v. formulation of APAP may be quite useful.

APAP Analgesic Efficacy

I.V. APAP vs Propacetamol

An i.v. prodrug of APAP, propacetamol, had been available in Europe for over 20 years [17]. Propacetamol is converted by plasma esterases immediately to APAP and diethylglycine, with 2 g propacetamol yielding approximately 1 g APAP. However, due to paracetamol's poor water solubility and low stability in solution, it is formulated as a lyophilized powder that must be dissolved in glucose or saline prior to infusion, and is associated with injection site pain in more than 50% of patients [48]. The development of a ready-to-use i.v. APAP formulation that does not require reconstitution [48], and is not associated with injection site pain as compared to placebo [17] rapidly replaced propacetamol. The reduced infusion site AEs observed with APAP is likely a reflection of pH and osmolarity values that are closer to or within physiologic ranges [48,63].

Overall, i.v. APAP demonstrated comparable efficacy to a bioequivalent dose of propacetamol in both children (15 mg/kg i.v. APAP ∼ 30 mg/kg propacetamol) and adults (1 g i.v. APAP ∼ 2 g propacetamol). The onset of efficacy for i.v. APAP and propacetamol was similar, occurring at approximately 15 minutes for both adults and children [48,63–66].

Macario and Royal performed a literature review of randomized clinical trials of i.v. APAP for acute postoperative pain [69]. Sixteen articles from nine countries published between 2005 and 2010 met inclusion criteria and had a total of 1,464 patients (Macario 2010). Four of the 16 articles had three arms in the study. One article had four arms. As a result, 22 study comparisons were analyzed: i.v. APAP to an active comparator (n = 8 studies) and i.v. APAP to placebo (n = 14 studies) [69]. The randomized controlled trials (RCTs) were of high methodological quality with Jadad median score = 5. In seven of eight active comparator studies (i.v. parecoxib [n = 3 studies], i.v. metamizol [n = 4], oral ibuprofen [n = 1]), i.v. APAP had similar analgesic outcomes as the active comparator [69]. Twelve of the 14 placebo studies found that i.v. APAP patients had improved analgesia. Ten of those 14 studies reported less opioid consumption, a lower percentage of patients rescuing, or a longer time to first rescue with i.v. APAP [69]. Macario and Royal concluded that in aggregate, these data indicate that i.v. APAP is an effective analgesic across a variety of surgical procedures [69].

I.V. NSAIDs

In a regional audit of six target National Health Service Hospitals within the south of the United Kingdom, i.v. NSAID administration was the preferred route of anti-inflammatory analgesics in the perioperative period largely because of its reliability and speed of onset [70]. Additionally, it was preferred in appropriate patients who were not permitted to take anything by mouth early in the perioperative period. The results of this audit also indicated significant use of i.v. NSAIDs not in accordance with manufacturers' recommendations.

Ketorolac

Ketorolac (Toradol) was the first parenteral NSAID for clinical analgesic use introduced in the United States. Studies have revealed that ketorolac is less effective as the sole postoperative analgesic in the management of moderate-to-severe postoperative pain [71,72]. Thus, as is the case with other i.v. nonopioids, its efficacy as analgesic monotherapy is usually insufficient particularly for severe pain after major surgery.

Keterolac Dosing

Since ketorolac has been marketed, there have been reports of death due to GI and operative site bleeding [73]. In the first 3 years after ketorolac was approved in the United States, 97 fatalities were reported [74]. As a consequence, the drug's license was suspended in Germany and France [75]. In a response to these events, the drug's manufacturer recommended reducing the dose of ketorolac from 150 to 120 mg per day [76]. The European Committee for Proprietary Medicinal products recommended a further maximal daily dose reduction to 60 mg for the elderly and to 90 mg for the nonelderly [77]. Currently, there is consensus that the maximum daily dose should be as low as 30 to 40 mg [78]. Furthermore, ketorolac is contraindicated as a preemptive analgesic before any major surgery and is contraindicated intraoperatively when hemostasis is critical because of its potential for prolonged PLT effects and increased risk of perioperative bleeding [71].

Ketorolac PKs

Ketorolac is almost entirely bound to plasma proteins (>99%), which results in a small apparent volume of distribution with extensive metabolism by conjugation and excretion via the kidney [79]. The mean plasma half-life is approximately 5.5 hours. The analgesic effect occurs within 30 minutes with maximum effect between 1 and 2 hours and duration of 4–6 hours [79].

Ketoralac—Analgesic Efficacy

Cassinelli and colleagues studied 25 patients who underwent a primary multilevel lumbar decompression procedure and were randomly assigned to receive either ketorolac or placebo in a double-blinded fashion [80]. There were no significant differences in available patient demographics, intraoperative blood loss, or postoperative Hemovac drain output between study groups. Morphine equivalent requirements were significantly less at all predetermined time points in addition to the overall hospital morphine requirement in patients randomized to receive ketorolac. Visual analog pain scores were significantly lower in patients randomized to receive ketorolac immediately postoperative in addition to 4, 12, and 16 hours postoperative. There were no identifiable postoperative complications associated with the use of ketorolac [80]. Cassinelli et al. concluded that i.v. ketorolac seems to be a safe and effective analgesic agent following multilevel lumbar decompressive laminectomy [80].

Ibuprofen

Ibuprofen, named from the now outdated nomenclature iso-butyl-propanoic-phenolic acid, is the most commonly used oral NSAID in the United States (primarily as an over-the-counter pain reliever). An i.v. formulation of ibuprophen (Caldolor; Cumberland Pharmaceuticals, Nashville, TN, USA) [81] was FDA approved in 2009. Ibuprofen is a racemic mixture of [−]R- and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S = isomer is responsible for clinical activity. The [−]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (∼60%) interconverted into the active [+]S species in adults. The enzymatic chiral inversion of ibuprofen is a three-step mechanism involving the formation of the acyl-CoA thioester by stereoselective activation of R-(–)-enantiomer in the presence of acyl-CoA sythetase (CoA) and enzymatic epimerization of the R-thioester to the S-(+)-thioester followed by the formation of S-(+)-enantiomer by hydrolysis of S-(+)-thioester [82,83]. Compounds demonstrating the same chiral inversion mechanisms as that of R-(−)-ibuprofen may inhibit the ibuprofen inversion and result in a decrease in the amount of S-(+)-ibuprofen formed [83]. The [−]R-isomer serves as a circulating reservoir to maintain levels of active drug.

Ibuprofen Dosing

The i.v. formulation is available in the United States as a 400 mg/4 mL or 800 mg/8 mL vial. Inactive ingredients include water and arginine (to increase its water solubility) (the lysine salt of ibuprofen—ibuprofen lysine [a different formulation], was released for i.v. use earlier in Europe). The concentration of arginine is 78 mg/mL and is present at a molar ratio of 0.92:1 (arginine : ibuprofen) [81]. The solution pH is approximately 7.4. Intravenous ibuprofen must be diluted with 0.9% or normal saline, 5% dextrose with water, or lactated Ringer's solution to a final concentration of 4 mg/mL or less prior to infusion, resulting in the following:

  • 400 mg dose: dilute 4 mL in no less than 100 mL of diluent (Albany Medical Center uses 200 mL)

  • 800 mg dose: dilute 8 mL in no less than 200 mL of diluent (Albany Medical Center uses 400 mL)

Diluted solutions are stable for up to 24 hours as ambient temperature (approximately 20 to 25°) and room lighting. Infusion time must be no less than 30 minutes [81].

Using a randomized, double-blind, placebo-controlled, single-dose, crossover study, Pavliv and colleagues found that the maximum plasma concentration (C(max)) of i.v. ibuprofen was approximately twice that of oral ibuprofen, and the (t(max)) of i.v. ibuprofen was 0.11 hour compared with 1.5 hours for oral ibuprofen. However, the elimination half-life of i.v and oral ibuprofen did not differ, both of which were approximately 2 hours. Oral ibuprofen was 100% bioavailable; therefore, the area under the concentration–time curve did not differ between i.v and oral ibuprofen. In addition, i.v. ibuprofen infused over 5 to 7 minutes did not differ in terms of safety or tolerability when compared with oral ibuprofen [84]. Although the package insert states to infuse over no less than 30 minutes, rapid infusion of i.v. ibuprofen over 5 to 7 minutes has also been shown to be safe and effective [84]. Thus, i.v. ibuprofen, when administered over 5 to 7 minutes in healthy subjects, achieved a higher C(max) and a more rapid t(max) than did oral ibuprofen and was found to be safe and well tolerated [84].

Although there are no suggested restrictions on the duration of therapy with i.v. ibuprofen, however, like all NSAIDs, it is recommended to use the lowest effective dose for the shortest possible duration. It is also recommended to use caution when initiating treatment with i.v. ibuprofen in patients with considerable dehydration.

Ibuprofen PKs

The PK parameters of i.v. ibuprofen determined with volunteers are presented in Table 1[81]. Ibuprofen, like most NSAIDs, is highly protein bound: >99% bound at 20 mcg/mL, and at concentrations >20 mcg/mL, binding is nonlinear [81]. The high degree of protein binding observed with NSAIDs limits the ability of these agents to enter the CNS. The metabolism of ibuprofen is predominantly via CYP2C9, and its primary route of clearance is renal excretion.

Table 1

Pharmacokinetic parameters of intravenous ibuprofen [82]

 400 mg* Caldolor 800 mg* Caldolor 
 Mean (CV%) Mean (CV%) 
 
 
Number of patients 12 12 
AUC (mcg·h/mL) 109.3 (26.4) 192.8 (18.5) 
Cmax (mcg/mL) 39.2 (15.5) 72.6 (13.2) 
KEL (1/h) 0.32 (17.9) 0.29 (12.8) 
T1/2 (h) 2.22 (20.1) 2.44 (12.9) 
 400 mg* Caldolor 800 mg* Caldolor 
 Mean (CV%) Mean (CV%) 
 
 
Number of patients 12 12 
AUC (mcg·h/mL) 109.3 (26.4) 192.8 (18.5) 
Cmax (mcg/mL) 39.2 (15.5) 72.6 (13.2) 
KEL (1/h) 0.32 (17.9) 0.29 (12.8) 
T1/2 (h) 2.22 (20.1) 2.44 (12.9) 
*

60 minute infusion time.

Cmax = Peak plasma concentration; CV = coefficient of variation; KEL = First-order elimination rate constant; T1/2 = elimination half-life.

Ibuprofen Analgesic Efficacy

Southworth et al. conducted a multicenter, randomized double-blind, placebo-controlled trial in 406 patients scheduled to undergo elective, single-site orthopedic or abdominal surgery, and suggested that ibuprofen 800 mg i.v. q6h was effective for postoperative pain management and was generally well tolerated with dizziness being the main AE [85].

Diclofenac

Diclofenac, a nonselective NSAID, is a weak acid (a phenylacetic acid derivative), with a pka of 4.0 and a partition coefficient into n-octanol from aqueous buffer, pH 7.4, of 13.4 [86]. After i.v. injection, plasma levels of diclofenac fell rapidly and were below the limits of detection at 5.5 hours postdosing. Individual drug profiles were described by a triexponential function, and mean half-lives of the three exponential phases were 0.05, 0.26, and 1.1 hours. After i.v. dosing, plasma levels, peak levels, and AUC were significantly reduced, and the volume of distribution was increased, as was the plasma clearance with coadministration of aspirin [87]. These observations were felt to be due in part to decreased protein binding and increased bilary excretion of diclofenac in the presence of salicylate. There are two i.v. diclofenac formulations available in Europe. The older parenteral formulation of diclofenac sodium (Voltarol ampoules) contains propylene glycol and benzyl alcohol as solubilizers (termed propyleneglycol-benzyl alcohol [PG-BA] diclofenac) but is still relatively insoluble. For i.v. use in postoperative pain, PG-BA diclofenac requires reconstitution for each patient, dilution to ≥100 mL, buffering and slow infusion over ≥30 minutes to minimize irritation. Despite these limitations, PG-BA diclofenac is used extensively as a result of its proven efficacy [88]. A newer formulation of diclofenac suitable for i.v. bolus injection (Dyloject) has been developed by complexing diclofenac sodium with hydroxypropyl β-cyclodextrin as a solubility enhancer (termed HPβCD diclofenac). This newer bolus diclofenac formulation was shown to be bioequivalent to the prior propylene glycol-based version which required an i.v. infusion over 30 minutes [89].

Diclofenac Dosing

HPβCD diclofenac may be given intramuscularly (IM) or i.v. Usual perioperative dosing is HPβCD diclofenac 37.5–75 mg i.v. every l2 hours after an initial bolus dose of 75 mg i.v./IM. HPβCD diclofenac is available as a pre-prepared formulation (solution) in a 2-mL vial (75 mg/2 mL) ready for immediate injection.

Diclofenac PKs

Following i.v. administration, a Cmax of 21, 524 ng/mL (including one aberrant value, approximately 10-fold higher than expected) for HPβCD diclofenac was attained at a median Tmax of 3 minutes (first assessment point) and a Cmax of 5,668 ng/mL for PG-BA was attained at a Tmax of 30 minutes (duration of the infusion) [90]. Diclofenac is highly bound (99.7%) to serum proteins, mainly albumin, and has a volume distribution of about 0.12–0.17 L/kg in healthy subjects [91,92]. Diclofenac is eliminated principally by metabolism and subsequent urinary and biliary excretion of glucuronide and sulfate conjugates of the metabolites [92]. The mean elimination half-life (t1/2) of HPβCD diclofenac was 1.17 hours after both i.v. bolus and intramuscular injection, while that for PG-BA diclofenac was 1.23 hours after i.v. infusion and 1.71 hours after intramuscular injection [90].

Diclofenac Analgesic Efficacy

Single-dose HPβCD diclofenac at a dose of 3.75, 9.4, 18.74, 25, 37.5, 50, and 75 mg administered by bolus injection produced significantly greater responses than placebo for total pain relief over 6 hours or pain intensity at 4 hours in the treatment of moderate or severe postoperative dental pain in randomized, double-blind trials. In this study, HPβCD diclofenac 37.5 and 75 mg were similar in efficacy to i.v. ketorolac 30 mg [89].

Other I.V. Nonselective NSAIDs

A number of other i.v. NSAIDs, such as ketoprofen, lornoxicam, and metamizol, are approved for use in Europe, but not in the United States. Metamizole (dipyrone) was available widely, including in the United States, but in the 1970s, it was discovered to be associated with the potential for agranulocytosis and was removed from the U.S. market [93]. It is still available in many countries in Europe and elsewhere. Generally, the efficacy of these products has been determined to be similar to more commonly used i.v. NSAIDs and i.v. COXIBs in postoperative clinical trials [94–98].

I.V. Selective COX-2 Inhibitors

While not available in the United States, i.v. parecoxib, a selective COX-2 inhibitor, was approved for use in Europe for short-term perioperative treatment of acute pain. Parecoxib is an inactive amide prodrug that undergoes rapid hydrolysis in vivo by liver esterase to valdecoxib [99]. It is not approved for use after cardiac surgery due to its risk of increased cardiovascular events. Parecoxib has no effect on PLT function and is not associated with increased postsurgical or GI bleeding.

Parecoxib Dosing

Parecoxib may be given IM or i.v. Usual perioperative dosing is parecoxib 20 mg-40 mg i.v. every 12 hours after an initial dose of 40 mg i.v./IM.

Parecoxib PKs

Following administration, parecoxib is rapidly and fully converted within 10 to 30 minutes to the active COX-2-specific moiety, valdecoxib, in vivo [100–103]. Previous studies in healthy subjects showed that single doses of up to 200 mg i.v. parecoxib are well tolerated and follow predictable PKs with a short plasma half-life (t1/2) of 0.3–0.7 hours for parecoxib and a terminal half-life of approximately 10 hours for the active moiety, valdecoxib [101]. Peak plasma levels of valdecoxib are achieved approximately 30 minutes after administration of parecoxib i.v. and roughly 1–1.5 hours after IM administration [101]. Valdecoxib is a substrate for hepatic cytochrome P450 3A4.

Parecoxib Analgesic Efficacy

Studies have generally demonstrated that i.v. parecoxib 40 mg q12h produced similar pain relief over 48 hours as conventional NSAIDs (metamizole) after open hysterectomy [104], and that single doses produced superior pain relief to placebo in same-day surgery cases [105]. In clinical trials, parecoxib has demonstrated analgesic efficacy in patients following laparotomy [106], orthopedic (knee) surgery [107], or oral surgery [108]. Furthermore, in clinical trials, parecoxib and valdecoxib had no effect on PLT aggregation in healthy elderly and nonelderly volunteers [109–111] and were associated with significantly lower incidences of gastroduodenal ulcers than standard doses of the nonspecific NSAIDs ketorolac, diclofenac, and naproxen [112–115].

Comparative Studies

I.V. APAP vs I.V. Nonselective NSAIDs

A few studies directly compared the efficacy of i.v. APAP to specific i.v. NSAIDs, and these studies will be discussed in the sections that follow (Table 2). Preliminary data indicate that analgesic efficacy of APAP is similar to NSAIDs and COXIBs when peripheral inflammation or inflammatory pain models are not being considered [124]. When peripheral inflammation is a significant component of pain, NSAIDs and COXIBs appear to be conferred a significant advantage over APAP.

Table 2

Comparative studies of perioperative nonopioid analgesics

Author/year Type of study Drugs compared Surgical procedure Sample size Results 
Lee et al., 2010 [116] Prospective R, DB, PC/AC parallel Placebo Total Thyroidectomy 20 All AC groups better pain scores and less rescue than control, satisfaction similar in all AC groups, IV APAP had similar analgesic efficacy to IV ketorolac 
IV APAP 20 
Ketorolac 20 
IV APAP + MS04 20 
Koppert et al., 2006 [117] Prospective R, PC Placebo Orthopedic surgery 25 IV APAP equivalent analgesic efficacy to IV parecoxib with significant decreased opioid use in first 24 hours 
Acetaminophen 25 
Parecoxib 25 
Ng et al., 2004 [118] Prospective R, DB, C Parecoxib Laparoscopic Sterilization 18 Early evaluation in PACU at waking and 1 hour post-operative ketorolac had better analgesic efficacy 
Ketorolac 17 
Leykin et al., 2008 [119] Prospective R, DB, C Parecoxib Nasal surgery 25 Parecoxib equal to ketorolac in analgesic efficacy, side effects, and patient satisfaction 
Ketorolac 25 
Grundmann et al., 2006 [120] Prospective R, DB, PC Placebo Lumbar Discectomy 20 Metamizol superior to parecoxib, APAP, and placebo for pain relief in PACU with infrequent side effects (P < 0.05) 
APAP 20 
Parecoxib 20 
Metamizol 20 
Kampe et al., 2006 [121] Prospective R, DB, C Acetaminophen Breast Cancer Surgery 20 IV APAP clinically equivalent to metamizol 
Metamizol 20 
Landwehr et al., 2005 [122] Prospective R, DB, PC Placebo Retina Surgery 13 IV APAP produced better pain relief than placebo and was comparable to IV metamizol 
Acetaminophen 12 
Metamizol 13 
Tiippana et al., 2008 [123] Prospective R, DB, C Intraop IV Parecoxib followed by PO Valdecoxib x7d Laparoscopic Cholecystectomy 40 IV APAP followed by oral APAP was as effective as IV parecoxib followed by oral valdecoxib but IV APAP reduced rescue use on first day (P < 0.001) 
Intraop IV APAP followed by PO APAP x7d 40 
Intraop IV Parecoxib followed by PO Valdecoxib x7d + IV Dexamethasone 10 mg 40 
Intraop IV APAP followed by PO APAP x7d + IV Dexamethasone 10 mg 40 
Author/year Type of study Drugs compared Surgical procedure Sample size Results 
Lee et al., 2010 [116] Prospective R, DB, PC/AC parallel Placebo Total Thyroidectomy 20 All AC groups better pain scores and less rescue than control, satisfaction similar in all AC groups, IV APAP had similar analgesic efficacy to IV ketorolac 
IV APAP 20 
Ketorolac 20 
IV APAP + MS04 20 
Koppert et al., 2006 [117] Prospective R, PC Placebo Orthopedic surgery 25 IV APAP equivalent analgesic efficacy to IV parecoxib with significant decreased opioid use in first 24 hours 
Acetaminophen 25 
Parecoxib 25 
Ng et al., 2004 [118] Prospective R, DB, C Parecoxib Laparoscopic Sterilization 18 Early evaluation in PACU at waking and 1 hour post-operative ketorolac had better analgesic efficacy 
Ketorolac 17 
Leykin et al., 2008 [119] Prospective R, DB, C Parecoxib Nasal surgery 25 Parecoxib equal to ketorolac in analgesic efficacy, side effects, and patient satisfaction 
Ketorolac 25 
Grundmann et al., 2006 [120] Prospective R, DB, PC Placebo Lumbar Discectomy 20 Metamizol superior to parecoxib, APAP, and placebo for pain relief in PACU with infrequent side effects (P < 0.05) 
APAP 20 
Parecoxib 20 
Metamizol 20 
Kampe et al., 2006 [121] Prospective R, DB, C Acetaminophen Breast Cancer Surgery 20 IV APAP clinically equivalent to metamizol 
Metamizol 20 
Landwehr et al., 2005 [122] Prospective R, DB, PC Placebo Retina Surgery 13 IV APAP produced better pain relief than placebo and was comparable to IV metamizol 
Acetaminophen 12 
Metamizol 13 
Tiippana et al., 2008 [123] Prospective R, DB, C Intraop IV Parecoxib followed by PO Valdecoxib x7d Laparoscopic Cholecystectomy 40 IV APAP followed by oral APAP was as effective as IV parecoxib followed by oral valdecoxib but IV APAP reduced rescue use on first day (P < 0.001) 
Intraop IV APAP followed by PO APAP x7d 40 
Intraop IV Parecoxib followed by PO Valdecoxib x7d + IV Dexamethasone 10 mg 40 
Intraop IV APAP followed by PO APAP x7d + IV Dexamethasone 10 mg 40 

AC = active comparator; APAP = acetaminophen; C = controlled; DB = double-blind; i.v. = intravenous; PO = per os (oral); PC = placebo-controlled; R = randomzied.

APAP vs Ketorolac

Lee et al. [116] was a randomized, active- and placebo-controlled, double-blind, parallel-group, 6-hour, single-dose study in 80 American Society of Anesthesiologists (ASA) I–II adult females (20–60 years old) scheduled for elective total thyroidectomy under standardized general anesthesia. Thirty minutes prior to the end of surgery, the patients were randomized into four groups of 20: i.v. APAP 1,000 mg, ketorolac 30 mg, i.v. APAP 700 mg plus morphine 3 mg, and saline (control group). A visual analog scale (VAS) was used to assess pain intensity and side effects (nausea, vomiting, headache, sedation, dizziness, and respiratory depression) at 0.5, 1, 2, 4, and 6 hours after study drug dosing. All three active groups had better pain scores and used less rescue at 0.5 and 1 hour than the control group (P < 0.05). Satisfaction was similar in the three active treatment groups compared to control. The authors concluded that i.v. APAP 1,000 mg produced similar analgesic efficacy to i.v. ketorolac 30 mg after thyroidectomy and may represent “an alternative to ketorolac for pain prevention after mild to moderately painful surgery in situations where the use of NSAIDs is unsuitable.”

In Ko et al. [125], 60 patients undergoing elective hand or forearm surgery were randomly assigned to one of three groups: the control group (C) received 0.5% lidocaine diluted with normal saline to 40 mL volume (n = 20) as an i.v. regional anesthesic block (IVRA); the APAP group (P for paracetamol) received IVRA lidocaine and APAP 300 mg admixture with saline to 40 mL (n = 20); and the ketorolac group (K) received IVRA lidocaine and ketorolac 10 mg admixture with saline to 40 mL (n = 20). The operative arm was elevated for 2 minutes and then exsanguinated with an Esmarch wrap and the double pneumatic tourniquet proximal cuff was inflated to 250 mm Hg and the study medications were administered. Sensory and motor block onset time, tourniquet pain, and analgesic use were assessed during operation. After tourniquet deflation, VAS (0–10) scores were assessed at 5, 10, 20, 30, and 40 minutes after deflation. Intermittent bolus fentanyl 1 µg/kg was used for pain treatment with VAS 3 or greater. The onset time of tourniquet pain (>3) was recorded as was total fentanyl consumption. After surgery, pain was assessed every 30 minutes for 2 hours in the postanesthesia care unit (PACU). Tramadol 50 mg was given for pain scores >3. Total tramadol consumption was recorded for the 2 hours in the PACU [125].

Sensory block onset time was shorter and tourniquet pain onset time was longer in the P group (APAP) compared to the control group (P < 0.05). The duration of sensory block and amount of fentanyl consumption were not different among the groups. Tourniquet pain scores were not different among the groups. Postoperative VAS scores were better in the K and P groups compared to control (P < 0.05) as was the number of patients who required supplemental tramadol and the total consumption of tramadol (P < 0.05 for each). The side effect profile was not significantly different among the groups. The authors observed that i.v. APAP added to a standard IVRA block could shorten onset time to sensory block, but APAP or ketorolac produces comparable postoperative pain relief [125].

APAP vs Ibuprofen

Published, peer-reviewed data comparing the efficacy of i.v. APAP and i.v. ibuprofen for analgesia are not available. Unlike the situation with NSAIDs, APAP's analgesic effect is due to a central site of action, resulting in the potential for the i.v. route to have a significant advantage over oral due to the earlier and higher peak CSF levels. As a result, the oral APAP data will not be predictive of outcome if head-to-head i.v. studies were to be conducted.

Similar to other NSAIDs, the use of i.v. ibuprofen is contraindicated in patients with known hypersensitivity to ibuprofen or NSAIDS and during the perioperative setting of coronary artery bypass graft surgery [81]. Patients with a history of ulcers, GI bleeding, fluid retention, heart failure, or patients that have renal impairment, heart failure, liver impairment, and patients taking diuretics or ACE inhibitors should be monitored closely due to an increased risk for cardiovascular or GI risks.

APAP vs Metamizol

Dipyrone (metamizole) is a NSAID used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in other countries including the United States because of an association with life-threatening blood agranulocytosis. Edwards and colleagues performed a 2010 Cochrane Review on single-dose dipyrone for acute postoperative pain which was updated from a 2001 Cochrane review [126]. There were no relevant new studies identified, but additional outcomes were sought [126]. Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g i.v. dipyrone (101), 2.5 g intramuscular dipyrone (99), with fewer than 60 participants receiving any other dose [126]. Over 70% of participants experienced at least 50% pain relief over 4 to 6 hours with oral dipyrone 500 mg compared to 30% with placebo in five studies (288 participants; number needed to treat [NNT] 2.4 [1.9 to 3.2]) [126].

Grundmann and colleagues conducted a prospective, double-blind, randomized, placebo-controlled study comparing the efficacy of three i.v. non-opioid analgesics for postoperative pain relief after lumbar microdiscectomy [120]. Eighty healthy patients were randomly divided into four treatment groups (n = 20 each) to receive either parecoxib 40 mg, paracetamol 1 g, metamizol 1 g, or placebo i.v. 45 minutes before the end of surgery. In the metamizol group, the pain score at arrival in the PACU was significantly lower compared with the paracetamol, parecoxib, and placebo groups. In addition, in the metamizol group, significantly fewer patients required additional patient-controlled analgesia compared with the other groups studied. The incidence of adverse side effects was infrequent in all groups [120].

Kampe and colleagues assessed the clinical efficacy of i.v. APAP 1 g and i.v. dipyrone 1 g on a 24-hour dosing schedule in this randomised, double-blinded study of 40 ASA I–III (American Society of Anesthesiologists classification of physical status) patients undergoing surgery for breast cancer [121]. Regarding pain scores at rest, the 90% confidence interval (CI) of the mean differences between the treatment groups over 30 hours postoperatively was found to be within the predefined equivalence margin [+7.5/−6.2], and the CI values for pain scores on coughing [+7.3/−9.0] were similar [121]. The two groups did not differ in cumulative opioid rescue consumption (Dipy Group 14.8 +/− 17.7 mg vs Para Group 12.1 +/− 8.8 mg, P = 0.54) nor in piritramide loading dose (Dipy Group 0.95 +/− 2.8 mg vs Para Group 1.3 +/− 2.8 mg, P = 0.545). Five patients in the Dipy Group experienced hypotension in contrast to none in the APAP Group (P = 0.047). There were no significant between-treatment differences for other adverse events, patient satisfaction scores (P = 0.4), or quality of recovery scores (P = 0.3) [121].

Landwehr and colleagues assessed clinical efficacy of i.v. APAP 1 g and i.v. metamizol 1 g on a 24-hour dosing schedule in this randomized, double-blinded, placebo-controlled study of 38 ASA physical status I–III patients undergoing retinal surgery [122]. They concluded that i.v. APAP 1 g has similar analgesic potency as i.v. metamizol 1 g for postoperative analgesia after retinal surgery [122].

I.V. Parecoxib vs I.V. APAP

Due to the specificity of COXIBs, parecoxib is associated with fewer bleeding complications than nonspecific NSAIDs, but potential risks for renal and cardiovascular events remain. For example, in a study comparing the renal effects of i.v. parecoxib and i.v. APAP vs placebo on elderly, post-orthopedic surgery patients, parecoxib demonstrated a significant transient reduction in creatinine clearance during the 2 hours following administration [117]. Clinically relevant decreases in glomerular filtration rate (GFR) may be experienced by patients suffering from concomitant diseases affecting renal function or aggravated by changes to the effective or actual circulating volume in an acute situation. Comparatively, as a result of its weak peripheral PG inhibition, i.v. APAP demonstrated no effect on GFR in patients with normal renal function and is recommended for use in patients with renal dysfunction. Secondary end points of the study (pain intensity and opioid consumption) illustrated that i.v. APAP 1 g and i.v. parecoxib 40 mg produced equivalent pain reductions over the 3 days treatment period; however, there was a numerical trend over 72 hours to decreased opioid consumption in the patient cohort treated with APAP with significant results in the first 24 hours [117].

One hundred sixty patients who underwent elective laparoscopic cholecystectomy were randomized by Tiippana and colleagues to four groups of 40 patients [123]. Groups 1 and 3 received parecoxib 40 mg i.v. during surgery and valdecoxib 40 mg × 1 PO for 7 postoperative days. Groups 2 and 4 received APAP 1 g × 4 i.v. during surgery and 1 g × 4 PO for 7 days. In addition, Groups 3 and 4 were given dexamethasone 10 mg i.v. intraoperatively. The patients were given oxycodone 0.05 mg/kg i.v. in phase 1 PACU (PACU 1) or 0.15 mg/kg PO in phase 2 PACU (PACU 2) as needed to keep VAS <3/10 [123]. Pain intensity, nausea, and the need of oxycodone in PACU 1 were similar in all groups [123]. Dexamethasone reduced the need of oral oxycodone in PACU 2 (7.0 +/− 1.0 mg vs 9.1 +/− 1.0 mg, P < 0.05). Pain intensity was similar in all groups at home. More patients in the parecoxib/valdecoxib groups needed rescue medication on the 1st postoperative day (P < 0.001) than paracetamol-treated patients [123]. Tiippana et al. concluded that APAP was as effective as parecoxib/valdecoxib for pain after laparoscopic cholecystectomy (LCC). Dexamethasone decreased the need of oxycodone in PACU 2. The effect of dexamethasone was similar in APAP and parecoxib/valdecoxib patients [123].

I.V. COXIBs vs I.V. Nonselective NSAIDs

Parecoxib vs Ketorolac

In short surgical procedures, rapid onset of analgesia is desired. While i.v. parecoxib may have a reduced risk of bleeding, the onset of analgesia may take longer than nonselective active NSAIDs because it requires 0.6 hour to achieve a therapeutic concentration [99]. To evaluate this effect, a double-blind, randomized, controlled trial was conducted to compare the efficacy of ketorolac and parecoxib following laparoscopic sterilization [118]. Thirty-six patients were randomized to receive either i.v. parecoxib (40 mg) or i.v. ketorolac (30 mg) at induction of anesthesia, and assessed for 3 hours postoperatively. At waking and 1 hour, pain scores were significantly higher for patients who received parecoxib. However, the number of patients requiring rescue analgesia was similar in the two treatment groups. The median time to rescue was numerically lower in, but clinically similar to, the parecoxib group [118]. Based upon these data, ketorolac may be preferable to parecoxib when rapid onset of analgesia is required (i.e., following a short surgical procedure). However, ketorolac use is limited due to bleeding complications especially when ketorolac is used at high doses or for more than 5 consecutive days [73,127]. In a different study, the two agents appeared to have equal analgesic efficacy.

Leykin and colleagues conducted a prospective, randomized, double-blind comparison between parecoxib (40 mg i.v. q8h) and ketorolac (3 mg i.v. q8h) for early postoperative analgesia following nasal surgery [119]. The AUC of the VAS calculated during the study period was 635 (26–1,413) in the parecoxib group and 669 (28–1,901) in the ketorolac group (P = 0.54). Rescue morphine analgesia was required by 12 patients (48%) in the parecoxib group and 11 patients (44%) in the ketorolac group (P < 0.05), while mean morphine consumption was 5 +/− 2.5 mg and 5 +/− 2.0 mg in ketorolac and parecoxib groups, respectively (P < 0.05). No differences in the incidence of side effects were recorded between the two groups [119]. Leykin et al. concluded that in patients undergoing endoscopic nasal surgery and local infiltration with 1% mepivacaine, parecoxib administered before discontinuing general anesthesia is as effective in treating early postoperative pain as ketorolac [119].

Combination Therapy (I.V. APAP/I.V. NSAID)

On occasion, it may be useful to combine APAP and an NSAID in an effort to achieve optimal analgesia while minimizing opioid analgesia (e.g., severe postoperative pain in a patient with obstructive sleep apnea and significant sensitivity to opioids). In a qualitative review, Hyllested and colleagues examined studies of APAP, NSAIDs, or their combination in postoperative pain management—irrespective of their route of administration [127]. They found that the addition of an NSAID to paracetamol may confer additional analgesic efficacy compared with paracetamol alone, and the limited data available also suggest that paracetamol may enhance analgesia when added to an NSAID, compared with NSAIDs alone [98]. In a qualitative systematic review of analgesic efficacy for acute postoperative pain, the combination of APAP and NSAID was more effective than APAP or NSAID alone in 85% and 64% of relevant studies, respectively [128]. The combination resulted in a reduction in pain intensity scores and rescue opioid consumption, 35.0 ± 20.9% and 38.8 ± 13.1%, respectively, vs APAP alone, and 37.7% ± 26.6% and 31.3% ± 13.4% lesser, respectively, vs an NSAID alone [128].

Safety/Tolerability of APAP Anti-inflammatory Agents

APAP

Aside from the known potential for hepatotoxicity with excessive dosing, APAP has a long history of safety. Intravenous APAP is safe, with an AE profile similar to placebo [44,48,50,129]. Significant AEs due to i.v. APAP use are rare and occur at an estimated rate of less than 1/10,000 [17]. Children exhibit a similar safety profile to adult populations [63,130–132].

Parra et al. [133] evaluated oral APAP 2,000 mg/day and 4,000 mg/day and found a minor, but still statistically significant, effect on international normalized ratio (INR) with the lower dose by day 7 of dosing compared to placebo in a study of 36 patients on a stable dose of warfarin. The mean maximum increase from baseline INR was approximately 0.6 (week 2) and 0.9 (week 3), respectively, for the 2,000 mg/day and 4,000 mg/day oral APAP groups. No studies have been performed specifically evaluating the short-term (<5 days) use of i.v. APAP in patients anticoagulated with warfarin; however, when taken together, the literature suggests monitoring may be appropriate in patients on warfarin when i.v. or oral APAP treatment is planned for more than several days.

APAP, regardless of route of administration, appears to have only limited potential for drug–drug interactions (Table 3) [134]. These interactions appear to be independent of route of administration. Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of APAP and increase its hepatotoxic potential. The clinical consequences of these effects have not been established. Effects of ethanol are complex because excessive alcohol usage can induce hepatic cytochromes, but ethanol also acts as a competitive inhibitor of the metabolism of APAP. The concomitant use of probenecid reduces APAP clearance, and salicylamide prolongs the elimination half-life, but the clinical relevance of these effects are unknown [17]. While older literature suggested that APAP may increase the risk for developing hepatotoxicity in patients already on hepatic inducing medications, such as barbiturates and anticonvulsants, a review of the literature found little evidence to support this assertion [135].

Table 3

Literature summary of drug–drug interactions with acetaminophen

Drug interaction mechanism Interaction potential 
Alcohol CYP2E1 inducer and substrate In theory, acetaminophen overdoses during the window of sudden abstinence may produce a risk of acetaminophen-induced hepatotoxicity. However, based upon the literature, it generally appears that therapeutic acetaminophen dosing is safe. 
Anticonvulsants Nonspecific hepatic inducer Published long-term studies failed to show that anticonvulsants induced acetaminophen-induced hepatotoxicity partly due to anticonvulsant-induced increased metabolism of acetaminophen through nontoxic (non-NAPQI producing) elimination pathways. 
Caffeine CYP1A2 substrate Enhances early exposure of oral acetaminophen, but is not expected to affect i.v. acetaminophen. 
Cimetidine CYP2E1 inhibitor May reduce NAPQI formation, but this effect may be minimal at therapeutic acetaminophen doses. Used with N-acetyl cysteine to treat oral acetaminophen overdoses to reduce NAPQI formation. 
Diflunisal Not characterized Increases acetaminophen levels by 50%, but the clinical significance is unknown. 
Isoniazid CYP2E1 inducer and substrate In theory, acetaminophen overdoses during the window of sudden abstinence may produce a risk of acetaminophen-induced hepatotoxicity. 
Serotonin-3 antagonists Pharmacodynamic interaction Potential antagonism of acetaminophen analgesic effect in experimental pain. Not demonstrated to occur in postoperative pain studies. 
Warfarin Pharmacodynamic interaction Acetaminophen may increase INR in patients taking warfarin. 
Drug interaction mechanism Interaction potential 
Alcohol CYP2E1 inducer and substrate In theory, acetaminophen overdoses during the window of sudden abstinence may produce a risk of acetaminophen-induced hepatotoxicity. However, based upon the literature, it generally appears that therapeutic acetaminophen dosing is safe. 
Anticonvulsants Nonspecific hepatic inducer Published long-term studies failed to show that anticonvulsants induced acetaminophen-induced hepatotoxicity partly due to anticonvulsant-induced increased metabolism of acetaminophen through nontoxic (non-NAPQI producing) elimination pathways. 
Caffeine CYP1A2 substrate Enhances early exposure of oral acetaminophen, but is not expected to affect i.v. acetaminophen. 
Cimetidine CYP2E1 inhibitor May reduce NAPQI formation, but this effect may be minimal at therapeutic acetaminophen doses. Used with N-acetyl cysteine to treat oral acetaminophen overdoses to reduce NAPQI formation. 
Diflunisal Not characterized Increases acetaminophen levels by 50%, but the clinical significance is unknown. 
Isoniazid CYP2E1 inducer and substrate In theory, acetaminophen overdoses during the window of sudden abstinence may produce a risk of acetaminophen-induced hepatotoxicity. 
Serotonin-3 antagonists Pharmacodynamic interaction Potential antagonism of acetaminophen analgesic effect in experimental pain. Not demonstrated to occur in postoperative pain studies. 
Warfarin Pharmacodynamic interaction Acetaminophen may increase INR in patients taking warfarin. 

APAP daily maximum dose recommendations have been driven by concerns over hepatotoxicity associated largely with uncontrolled outpatient use [43]. Patients with severe hepatic disease are also at an increased risk for hepatotoxicity, but glutathione deficiency does not appear to be an additional risk factor [44]. Overall, the risk of adverse events or hepatotoxicity is extremely rare with therapeutic use [44]. Patients with high alcohol consumption or are fasting who ingest toxic doses of APAP appear to be at increased risk of developing hepatotoxicity [18,136–141], but those taking appropriate therapeutic doses of APAP do not seem to be at overly excessive clinically significant risks.

NSAIDs

The use of NSAIDS may be associated with renal impairment, GI effects, blood clotting disorders, and cardiovascular events [33,43]. COX-2 is constitutively expressed in kidney and vascular endothelium where it plays a role in the maintenance of vascular integrity [142]. Therefore, NSAIDs that target COX-2 may increase the risk for renal impairment and toxicity. Short-term treatment with ibuprofen or ketorolac results in a minimal impact on normal renal function [143–145]. For example, a systematic review of patients receiving diclofenac, ketorolac, indomethacin, or ibuprofen for 3 days postoperatively did not find an increased incidence of renal failure [146]. Although short-term use of NSAIDs for the management of acute pain does not seem to impair renal function [146], there are numerous reports of NSAID-induced renal failure when these drugs are utilized for the perioperative management of pain [147–152]. A transient reduction in renal function was observed on postoperative day 1 as measured by reduced creatinine clearance, sodium output, and potassium output, although values returned to normal on day 2 [146]. However, patients receiving ketorolac are at a dramatically increased risk of renal failure if treatment is extended beyond 5 days [153]. Additionally, ibuprofen and ketorolac may increase the risk for toxicity when administered concomitantly with aminoglycosides [154] or cyclosporine [155]. The risk of renal toxicity also increases in children with hypovolemia, hypotension, or preexisting renal disease [43].

GI AEs of NSAIDs include ulcer formation and bleeding. Inhibition of COX in the epithelium of the stomach leads to a reduction in PGs and a subsequent increase in sensitivity to gastric acid. This can cause hemorrhages and erosions of the gastric epithelium [118]. Short-term use of NSAIDs (<1 week) has a reduced risk of developing serious GI events, although these events may occur at any time [142,156,157]. There have been multiple reports of GI ulceration or bleeding associated with brief exposure to NSAIDs for the perioperative management of pain [158–162]. Patients are at an increased risk for developing adverse GI events if they have peptic ulcer disease, Helicobacter pylori infection, or if they are of an advanced age [163–165].

Perioperative Issues of Selective COX-2 Inhibitors

Selective COXIBs, such as parecoxib, are associated with less gastric toxicity and fewer bleeding complications than NSAIDs, and are safe for perioperative use in noncardiac surgery [163,165–167]. The risk of renal insult is roughly the same as with traditional NSAIDs; however, of particular concern is the increased risk of cardiovascular adverse events observed in patients treated with COX-2 inhibitors. Patients who received oral rofecoxib had an almost fivefold increased risk of myocardial infarction [133] and an increased risk of atherothrombotic complications after 18 months of rofecoxib intake [168], and this appears to be a class effect, although different agents seem to possess different degrees of risk. Therefore, COX-2 inhibitors should be avoided in the perioperative period of coronary artery bypass graft surgery and those patients who are at an increased risk for thrombotic events [141,163,169,170]. An assessment for the risk of a cardiovascular event should be performed before patients are treated with a COX-2 inhibitor.

Clinicians may prescribe low-dose aspirin in conjunction with COX-2 inhibitors in efforts to interfere with any prothrombotic COXIB tendencies. Rimon and colleagues reported the surprising observation that celecoxib and other COXIBs may bind tightly to a subunit of COX-1 [171]. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of arachidonic acid (AA) by the second partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo PLT aggregation. Because COXIBs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. It is important to know that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted by COXIBs [171].

Perioperative Bleeding

Perioperative bleeding may be induced or exacerbated by concomitant medications that have the potential for interference with surgical hemostasis. For example, when used as a perioperative analgesic, a single dose of a NSAID with significant COX-1 effect may cause prolonged PLT dysfunction [23,172].

APAP 15 mg/kg may produce a dose-dependent, transient, and minor effect on PLTs due to a weak inhibition of PLT COX-1 [172]. However, PLT dysfunction is far more pronounced with the NSAIDs [45,173]. In a study of 107 patients undergoing elective tonsillectomy [174], the authors reported that a single dose of i.v. APAP of 3,000 mg did not cause a significant effect on PLT aggregation, whereas diclofenac 75 mg caused a profound effect and was associated with one patient who required treatment for postoperative bleeding. Note that a single dose of i.v. ketorolac 0.4 mg/kg, the equivalent of a 30 mg in a 70 kg adult, has the potential to cause PLT dysfunction for at least 24 hours [45].

PLTs are especially vulnerable to COX-1 inhibition because unlike most other cells, they are not capable of regenerating this enzyme. Presumably, this reflects the inability of PLTs to independently synthesize proteins. This means that aspirin, which irreversibly acetylates COX, causes inhibition of PLT aggregation for the lifespan of the PLT which is 10 to 14 days [175]. In contrast, nonselective NSAIDs reversibly inhibit the COX enzyme, causing a transient reduction in the formation of thromboxane A2 (TXA2) and inhibition of PLT activation which resolves after most of the drug is eliminated [175]. The use of NSAIDs may result in antiplatelet effects and an increased incidence of perioperative blood loss and blood transfusion requirements, resulting in increased morbidity and mortality following a variety of surgical procedures. COXIBs have no significant effects on PLT function at therapeutic dosages [176,177]. For these reasons, the perioperative administration of COXIBs or APAP may be a safer alternative to NSAIDs in certain surgical procedures where increased bleeding is a concern (e.g., total joint arthroplasty, tonsillectomy) [178–191].

Hong et al. evaluated PLT function in 10 healthy volunteers and performed a population pharmacodynamic modeling of aspirin and ibuprofen-induced PLT aggregation inhibition [192]. The authors showed that at an oral dose of 400 mg, ibuprofen's PLT inhibition was significant, lasting 6 to 8 hours. Therefore, when ibuprofen is dosed q6h, PLT function will remain significantly reduced until the drug is discontinued.

Niemi and colleagues reported on their evaluation of the effect on PLT function in healthy volunteers administered single doses of i.v. ketoprofen 1.4 mg/kg, i.v. ketorolac 0.4 mg/kg, and i.v. diclofenac 1.1 mg/kg [173]. Diclofenac produced mild reversible impairment in PLT aggregation and no prolongation in bleeding time, whereas ketoprofen and ketorolac produced both PLT dysfunction and prolonged bleeding time. The single dose effects of ketorolac continued for 24 hours. The anti-PLT effects of ketorolac were confirmed in a placebo-controlled study in 10 healthy adults given a single dose of i.v. ketorolac 0.4 mg/kg or placebo. Ketorolac caused clinically meaningful PLT dysfunction for 24 hours [45]. In an active-controlled crossover study in 10 volunteers, i.v. ketoprofen 1.4 mg/kg and i.v. ketorolac 0.4 mg/kg caused significant PLT dysfunction and prolonged bleeding time, whereas i.v. diclofenac 1.1 mg/kg had a modest transient effect [193]. NSAID-induced PLT dysfunction is dose proportional. For example, in a study with oral ibuprofen, doses of 200, 400, 800, and 1,200 mg produced 93, 94, 98, and 99% inhibition, respectively [194].

Under normal circumstances, there is no significant concentration of COX-2 in PLTs; there, COX-2 selective inhibitors are less likely to lead to PLT dysfunction. Knijff-Dutmer and colleagues demonstrated in patients with rheumatoid arthritis that naproxen 500 mg bid for 2 weeks significantly reduced PLT aggregation and prolonged bleeding time compared to meloxicam, an NSAID which at low doses exhibits preferential inhibition of COX-2 over COX-1 [195].

Graff and colleagues studies the effects of parecoxib and dipyrone (metamizol, an NSAID no longer available in the United States) on PLT aggregation in patients undergoing meniscectomy: a double-blind, randomized, parallel-group study [196]. PLT aggregation and thromboxane B2 (TXB2) formation were significantly lower for 6 hours in dipyrone-treated patients compared with parecoxib-treated patients [196]. In contrast, TXB2 formation was increased with parecoxib 6 hours after administration compared with pretreatment values. Thus, parecoxib did not affect PLT aggregation in a population of patients undergoing routine partial meniscectomy (or a similar arthroscopic procedure) under clinical conditions.

Acetylsalicylic acid and ketorolac both substantially disrupted PLT function in contrast to i.v. diclofenac 37.5 mg or oral diclofenac 50 mg control. Diclofenac, with its balanced COX-1 and COX-2 inhibitory profile, may pose less risk of postoperative bleeding than NSAIDs such as ketorolac and ASA, which predominantly inhibit COX-1 [197].

Perhaps, the more important question is whether the measurable impairment in PLT function or increase in bleeding time translates into a problem with surgical hemostasis or a readmission to treat postoperative bleeding. While the published data are conflicting, a recent 15-year audit of post-tonsillectomy bleeding and readmission rates for treatment demonstrated a year-over-year increase in bleeding rates paralleling routine perioperative use of NSAIDs or corticosteroids, such as dexamethasone, used to reduce postoperative nausea and vomiting [198].

Conclusion

Multimodal or balanced analgesia, the combination of nonopioid analgesics and/or regional analgesic techniques with an opioid, has been proposed as a way to decrease systemic opioid consumption and to improve postoperative analgesia after surgeries likely to result in severe pain [11,199–202]. The potential benefits of a multimodal approach include clinically meaningful pain relief with reduced consumption of opioids that may result in a reduced frequency and severity of unwanted opioid-related AEs and an overall improvement of patient satisfaction and health outcomes, such as earlier ambulation and discharge.

APAP is a safe, well-tolerated, and effective analgesic for both adults and children. The introduction of ready-to-use i.v. APAP has provided a formulation that achieves more consistent and more rapid therapeutic levels than orally or rectally administered APAP. Intravenous APAP also has a postoperative opioid-sparing effect. Efficacy of a given drug must always be measured against the safety profile and tolerability of that drug. Specifically, direct comparisons of APAP and NSAIDs and other nonopioid therapeutic agents need to be evaluated in the context of the variables affecting time to peak concentration required for various formulations, interpatient variability, and age-related factors affecting antipyretic effects and for analgesic effects. In addition, the type of procedure studied can affect perceived efficacy [9]. Adverse events associated with APAP are comparable to placebo, with only mild effects on PLT aggregation and no clearly demonstrated, clinically significant drug interactions. With therapeutic dosing, hepatotoxicity is rare. Intravenous APAP is a viable alternative to NSAIDS for rapid analgesia, and is associated with a lower incidence of adverse events. A single dose of a COX-1 NSAID may produce prolonged PLT dysfunction and increased risk of surgical bleeding for up to 24 hours. Therefore, i.v. APAP may be the preferred nonopioid analgesic where surgical bleeding is a concern.

In addition, APAP is not associated with the adverse GI events that occur with nonselective NSAIDs or with the cardiovascular adverse events that occur with the selective COX-2 inhibitors. Intravenous APAP represents a safe and effective first-line agent for the treatment of acute mild-to-moderate pain in the perioperative period when oral agents may be impractical or when rapid onset with predictable therapeutic dosing is required.

Acknowledgments

The author thanks Mike A. Royal, MD (Cadence Pharmaceuticals, Inc.), Michaela Ryan, PhD, and Pya Seidner for assistance in the preparation of the manuscript.

The author does not have commercial affiliations that might pose a conflict of interest, did not receive any financial support for preparing this article, and has no financial information to disclose.

References

1
Apfelbaum
JL
Chen
C
Mehta
SS
Gan
TJ
.
Postoperative pain experience: Results from a national survey suggest postoperative pain continues to be undermanaged
.
Anesth Analg
 
2003
;
97
:
534
40
.
2
Warfield
CA
Kahn
CH
.
Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults
.
Anesthesiology
 
1995
;
83
:
1090
4
.
3
Kehlet
H
Dahl
JB
.
Anaesthesia, surgery, and challenges in postoperative recovery
.
Lancet
 
2003
;
362
:
1921
8
.
4
Desborough
JP
.
The stress response to trauma and surgery
.
Br J Anaesth
 
2000
;
85
:
109
17
.
5
Wilmore
DW
.
From Cuthbertson to fast-track surgery: 70 years of progress in reducing stress in surgical patients
.
Ann Surg
 
2002
;
236
:
643
8
.
6
Holte
K
Kehlet
H
.
Postoperative ileus: A preventable event
.
Br J Surg
 
2000
;
87
:
1480
93
.
7
Closs
SJ
.
Patients' night-time pain, analgesic provision and sleep after surgery
.
Int J Nurs Stud
 
1992
;
29
:
381
92
.
8
Perkins
FM
Kehlet
H
.
Chronic pain as an outcome of surgery. A review of predictive factors
.
Anesthesiology
 
2000
;
93
:
1123
33
.
9
Nikolajsen
L
Minella
CE
.
Acute postoperative pain as a risk factor for chronic pain after surgery
.
Eur J Pain Suppl
 
2009
;
3
:
29
32
.
10
Vermelis
J
Wassen
M
Fiddelers
A
Nijhues
J
Marcus
M
.
Prevlaence and predictors of chronic pain after labor and delivery
.
Curr Opin Anaesthesiol
 
2010
;
23
:
295
9
.
11
Kehlet
H
Dahl
JB
.
The value of “multimodal” or “balanced analgesia” in postoperative pain treatment
.
Anesth Analg
 
1993
;
77
:
1048
56
.
12
Dahl
JB
Rosenberg
J
Dirkes
WE
Morgensen
T
Kehlet
HL
.
Prevention of postoperative pain by balanced analgesia
.
Br J Anaesth
 
1990
;
64
:
518
20
.
13
Kehlet
H
Wilmore
DW
.
Multimodal strategies to improve surgical outcome
.
Am J Surg
 
2002
;
183
:
630
41
.
14
Buvanendran
A
Kroin
JS
Tuman
KJ
et al
Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor of pain management and recovery of function after knee replacement
.
JAMA
 
2003
;
290
:
2411
8
.
15
Ashburn
MA
Caplan
RA
Carr
DB
et al
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
 
2004
;
100
:
1573
81
.
16
United States Acute Pain Management Guideline Panel
.
Acute Pain Management: Operative Or Medical Procedures and Trauma
 , Pub. no. 92-0032.
Rockville, MD
:
United States Department of Health and Human Services, Public Health Service Agency for Health Care Policy and Research
;
1992
.
17
Duggan
ST
Scott
LJ
.
Intravenous paracetamol (acetaminophen)
.
Drugs
 
2009
;
69
:
101
13
.
18
Graham
GG
Scott
KF
day
RO
.
Tolerability of paracetamol
.
Drug Saf
 
2005
;
28
:
227
40
.
19
Barden
J
Edwards
J
Moore
A
McQuay
H
.
Single dose oral paracetamol (acetaminophen) for postoperative pain
.
Cochrane Database Syst Rev
 
2004
;(
1
):
CD004602
.
20
Weil
K
Hooper
L
Afzal
Z
et al
Paracetamol for pain relief after surgical removal of lower wisdom teeth
.
Cochrane Database Syst Rev
 
2007
;(
3
):
CD004487
.
21
Toms
L
McQuay
HJ
Derry
S
Moore
RA
.
Single dose oral paracetamol (acetaminophen) for postoperative pain in adults
.
Cochrane Database Syst Rev
 
2008
;(
4
):
CD004602
.
22
Anderson
BJ
.
Paracetamol (Acetaminophen): Mechanisms of action
.
Paediatr Anaesth
 
2008
;
18
:
915
21
.
23
Vane
JR
Bottin
RM
.
New insights into the mode of action of anti-inflammatory drugs
.
Inflamm Res
 
1995
;
44
:
1
10
.
24
Mitchell
JA
Akarasereenont
P
Thiemermann
C
Flower
RJ
Vane
JR
.
Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase
.
Proc Natl Acad Sci USA
 
1993
;
90
:
11693
7
.
25
Bartfai
T
.
Telling the brain about pain
.
Nature
 
2001
;
410
:
425
6
.
26
Buvanendran
A
Kroin
JS
Tuman
KJ
et al
Cerebrospinal fluid and plasma pharmacokinetics of the cyclooxygenase 2 inhibitor rofecoxib in humans: Single and multiple oral drug administration
.
Anesth Analg
 
2005
;
100
:
1320
4
.
27
Dembo
G
Park
SB
Kharasch
ED
.
Central nervous system concentration of cyclooxygenase-2 inhibitors in humans
.
Anesthesiol
 
2005
;
102
:
409
15
.
28
Bonati
M
Kanto
J
Tognoni
G
.
Clinical pharmacokinetics of cerebrospinal fluid
.
Clin Pharmacokinet
 
1982
;
7
:
312
35
.
29
Mannila
A
Kumpulainen
E
Lehtonen
M
et al
Plasma and cerebrospinal fluid concentrations of indomethacin in children after intravenous administration
.
J Clin Pharmacol
 
2007
;
47
:
94
100
.
30
Kokki
H
Kumpulainen
E
Lehtonen
M
et al
Cerebrospinal fluid distribution of ibuprofen after intravenous administration in children
.
Pediatr
 
2007
;
120
:
e1002
8
.
31
Kokki
H
Karvinen
M
Jekunen
A
.
Diffusion of ketoprofen into the cerebrospinal fluid of young children
.
Paediatr Anaesth
 
2002
;
12
:
313
6
.
32
Mannila
A
Kokki
H
Heikkinen
M
et al
Cerebrospinal fluid distribution of ketoprofen after intravenous administration in young children
.
Clin Pharmacokinet
 
2006
;
45
:
737
43
.
33
Lee
WM
.
Acetaminophen toxicity: Changing perceptions on a social/medical issue
.
Hepatology
 
2007
;
46
:
966
70
.
34
Smith
HS
.
Potential analgesic mechanisms of acetaminophen
.
Pain Phys
 
2009
;
12
:
269
80
.
35
Kumpulainen
E
Kokki
H
Halonen
T
et al
Paracetamol (acetaminophen) penetrates readily into the cerebrospinal fluid of children after intravenous administration
.
Pediatrics
 
2007
;
119
:
766
71
.
36
Boutaud
O
Aronoff
DM
Richardson
JH
Marnett
LJ
Oates
JA
.
Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases
.
Proc Natl Acad Sci USA
 
2002
;
99
:
7130
5
.
37
Pickering
G
Esteve
V
Loriot
MA
Eschalier
A
Dubray
C
.
Acetaminophen reinforces descending inhibitory pain pathways
.
Clin Pharmacol Ther
 
2008
;
84
:
47
51
.
38
Ottani
A
Leone
S
Sandrini
M
Ferrari
A
Bertolini
A
.
The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors
.
Eur J Pharmacol
 
2006
;
531
:
280
1
.
39
Björkman
R
.
Central antinociceptive effects of nonsteroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat
.
Acta Anaesthesiol Scand Suppl
 
1995
;
103
:
1
44
.
40
Hogestatt
ED
Jönsson
BA
Ermund
A
et al
Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system
.
J Biol Chem
 
2005
;
280
:
31405
12
.
41
Björkman
R
Hallman
KM
Hedner
J
Hedner
T
Henning
M
.
Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P
.
Pain
 
1994
;
57
:
259
64
.
42
Bujalska
M
.
Effect of nitric oxide synthase inhibition on antinociceptive action of different doses of acetaminophen
.
Pol J Pharmacol
 
2004
;
56
:
605
10
.
43
Anderson
BJ
.
Comparing the efficacy of NSAIDs and paracetamol in children
.
Paediatr Anaesth
 
2004
;
14
:
201
17
.
44
Oscier
CD
Milner
QJ
.
Peri-operative use of paracetamol
.
Anaesthesiology
 
2009
;
64
:
65
72
.
45
Niemi
TT
Backman
JT
Syrjälä
MT
Viinikka
LU
Rosenberg
PH
.
Platelet dysfunction after intravenous ketorolac or propacetamol
.
Acta Anaesthesiol Scand
 
2000
;
44
:
69
74
.
46
Hinz
B
Cheremina
O
Brune
K
.
Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man
.
FASEB J
 
2008
;
22
:
383
90
.
47
Graham
GG
Scott
KF
.
Mechanism of action of paracetamol
.
Am J Ther
 
2005
;
12
:
46
55
.
48
Moller
PL
Juhl
GI
Payen-Champenois
C
Skoglund
LA
.
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
:
90
6
.
49
Moller
PL
Sindet-Pedersen
S
Petersen
CT
et al
Onset of acetaminophen analgesia: Comparison of oral and intravenous routes after third molar surgery
.
Br J Anaesth
 
2005
;
94
:
642
8
.
50
Sinatra
RS
Jahr
JS
Reynolds
LW
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
:
822
31
.
51
Atef
A
Fawaz
AA
.
Intravenous paracetamol is highly effective in pain treatment after tonsillectomy in adults
.
Eur Arch Otorhinolaryngol
 
2008
;
265
:
351
5
.
52
Perfalgan [package insert]
.
Uxbridge
 .
Middlesex, UK
:
Bristol-Myers Squibb Pharmaceuticals Ltd
;
2007
.
53
Holmér Pettersson
P
Owall
A
Jakobsson
J
.
Early bioavailability of paracetamol after oral or intravenous administration
.
Acta Anaesthesiol Scand
 
2004
;
48
:
867
70
.
54
Anderson
BJ
Woolard
GA
Holford
NH
.
Pharmacokinetics of rectal paracetamol after major surgery in children
.
Paediatr Anaesth
 
1995
;
5
:
237
42
.
55
Anderson
BJ
Holford
NH
Woollard
GA
Kanagasundaram
S
Mahadevan
M
.
Perioperative pharmacodynamics of acetaminophen analgesia in children
.
Anesthesiology
 
1999
;
90
:
411
21
.
56
Birmingham
PK
Tobin
MJ
Fisher
DM
et al
Initial and subsequent dosing of rectal acetaminophen in children: A 24-hour pharmacokinetic study of new dose recommendations
.
Anesthesiology
 
2001
;
94
:
385
9
.
57
Rømsing
J
Møiniche
S
Dahl
JB
.
Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia
.
Br J Anaesth
 
2002
;
88
:
215
26
.
58
Schutz
R
Fong
L
Chang
Y
Royal
M
.
Open-label, 4-Period, Randomized, Crossover Study to Determine the Comparative Pharmacokinetics of Oral and Intravenous Acetaminophen Administration in Healthy Male Volunteers
 . Poster presentation ASRA spring meeting, April 19–22,
2007
, Vancouver, BC, Canada.
59
Gibb
IA
Anderson
BJ
.
Paracetamol (acetaminophen) pharmacodynamics: Interpreting the plasma concentration
.
Arch Dis Child
 
2008
;
93
:
241
7
.
60
Gazzard
BG
Ford-Hutchinson
AW
Smith
MJH
Williams
R
.
The binding of paracetamol to plasma proteins of man and pig
.
J Pharm Pharmacol
 
1973
;
25
:
964
7
.
61
Jensen
LL
Handberg
G
Brosen
K
Schmedes
A
Ording
H
.
Paracetamol concentrations in plasma and cerebrospinal fluid
.
Eur J Anaesthesiol
 
2004
;
21
:
193
.
62
Bannwarth
B
Netter
P
Lapicque
F
et al
Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol
.
Br J Clin Pharmacol
 
1992
;
34
:
79
81
.
63
Murat
I
Baujard
C
Foussat
C
et al
Tolerance and analgesic efficacy of a new i.v. paracetamol solution in children after inguinal hernia repair
.
Paediatr Anaesth
 
2005
;
15
:
663
70
.
64
Wilson
JT
Brown
RD
Bocchini
JA
Jr
Kearns
GL
.
Efficacy, disposition and pharmacodynamics of aspirin, acetaminophen and choline salicylate in young febrile children
.
Ther Drug Monit
 
1982
;
4
:
147
80
.
65
Brown
RD
Kearns
GL
Wilson
JT
.
Integrated pharmacokinetic-pharmacodynamic model for acetaminophen, ibuprofen, and placebo antipyresis in children
.
J Pharmacokinet Biopharm
 
1998
;
26
:
559
79
.
66
Rømsing
J
Ostergaard
D
Senderovitz
T
et al
Pharmacokinetics of oral diclofenac and acetaminophen in children after surgery
.
Paediatr Anaesth
 
2001
;
11
:
205
13
.
67
Jarde
O
Boccard
E
.
Parental versus oral route increases paracetamol efficacy
.
Clin Drug Invest
 
1997
;
14
:
474
81
.
68
Royal
M
Fong
L
Smith
H
et al
Randomized Study of the Efficacy and Safety of IV Acetaminophen Compared to Oral Acetaminophen for the Treatment of Fever
 . Poster presentation at Hospital Medicine 2009 (Society for Hospital Medicine), Chicago, IL, May 14–17,
2009
.
69
Macario
A
Royal
MA
.
A Literature Review of Randomized Clinical Trials of Intravenous Acetaminophen (Paracetamol) for Acute Postoperative Pain
.
Pain Pract
 
2010
Nov 28; doi: ).
70
Allen
SC
Ravindran
D
.
Perioperative use of nonsteroidal anti-inflammatory drugs: Results of a UK regional audit
.
Clin Drug Investig
 
2009
;
29
:
703
11
.
71
Power
I
Noble
DW
Douglas
E
Spence
AA
.
Parenteral ketorolac tromethamine and morphine sulphate for pain relief after cholecystectomy
.
Br J Anaesth
 
1990
;
65
:
448
55
.
72
Cepeda
MS
Vargas
L
Ortegon
G
Sanchez
MA
Carr
DB
.
Comparative analgesic efficacy of patient-controlled analgesia with ketorolac versus morphine after elective intraabdominal operations
.
Anesth Analg
 
1995
;
80
:
1150
3
.
73
Strom
BL
Berlin
JA
Kinman
JL
et al
Parenteral ketorolac and risk of gastrointestinal and operating site bleeding. A postmarketing surveillance study
.
JAMA
 
1996
;
275
:
376
82
.
74
Reinhart
DJ
.
Minimizing the adverse effects of ketorolac
.
Drug Safety
 
2000
;
22
:
487
97
.
75
Lewis
S
.
Ketorolac in Europe
.
Lancet
 
1994
;
343
:
784
.
76
Toradol IV/IM [Package insert]
. Nutley, NJ: Roche Laboratories,
1994
.
77
Choo
V
Lewis
S
.
Ketorolac doses reduced
.
Lancet
 
1993
;
10
:
109
.
78
Sevarino
FB
Sinatra
RS
Paige
D
et al
The efficacy of intramuscular ketorolac in combination with intravenous PCA morphine for postoperative pain relief
.
J Clin Anesth
 
1992
;
4
:
285
8
.
79
Gillis
JC
Brogden
RN
.
Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management
.
Drugs
 
1997
;
53
:
139
88
.
80
Cassinelli
EH
Dean
CL
Garcia
RM
Furey
CG
Bohlman
HH
.
Ketorolac use for postoperative pain management following lumbar decompression surgery: A prospective, randomized, double-blinded, placebo-controlled trial
.
Spine
 
2008
;
33
:
1313
7
.
81
Caldolor [prescribing information]
. Nashville, TN: Cumberland Pharmaceuticals Inc;
2009
.
82
Sanins
SM
Adams
WJ
Kaiser
DG
et al
Mechanistics studies on the metabolic chiral inversion of R-ibuprofen in the rat
.
Drug Metab Dispos
 
1991
;
19
:
405
10
.
83
Reddy
A
Hashim
M
Wang
Z
et al
A novel method for assessing inhibition of ibuprofen chiral inversion and its application in drug discovery
.
Intl J Pharmaceutics
 
2007
;
335
:
63
9
.
84
Pavliv
L
Voss
B
Rock
A
.
Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults
.
Am J Health Syst Pharm
 
2011
;
68
:
47
51
.
85
Southworth
S
Peters
J
Rock
A
Pavliv
L
.
A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain
.
Clin Ther
 
2009
;
31
:
1922
35
.
86
Willis
JV
Kendall
MJ
Flinn
RM
Thornhill
DP
Welling
PG
.
The Pharmacokinetics of Diclofenac Sodium Following Intravenous and Oral Administration
.
Eur J Clin Pharmacol
 
1979
;
16
:
405
10
.
87
Willis
JV
Kendall
MJ
Jack
DB
.
A study of the effect of aspirin on the pharmaokinetics of oral and intravenous diclofenac sodium
.
Eur J Clin Pharmacol
 
1980
;
18
:
415
8
.
88
Leeson
RM
Harrison
S
Ernst
CC
et al
Dyloject, a novel injectable diclofenac formulation, offers greater safety and efficacy than Voltarol for postoperative dental pain
.
Reg Anesth Pain Med
 
2007
;
32
:
303
10
.
89
McCormack
PL
Scott
LJ
.
Diclofenanc sodium injection (Dyloject): In postoperative pain
.
Drugs
 
2008
;
68
:
123
30
.
90
Javelin Pharmaceuticals Inc
.
A phase 1, randomized, analytically blind, fasted, single-dose, four-way crossover study of the bioavailability of one dose level of parenteral DIC075V (diclofenac sodium 75 mg/2 ml), administered intramuscularly and intravenously, vs. parenteral VoltarolR (diclofenac sodium 75 mg/3 ml) administered intramuscularly and intravenously in healthy adult volunteers
 . New York: Javelin Pharmaceuticals Inc.,
2004
. (Data on file).
91
Todd
PA
Sorkin
EM
.
Diclofenac sodium: A reappraisal pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy
.
Drugs
 
1988
;
35
:
244
85
.
92
Brogden
RN
Heel
RC
Pakes
GE
Speight
TM
Avery
GS
.
Diclofenac sodium: A review of its pharmacological properties and therapeutic use in rheumatic diseases and pain of varying origin
.
Drugs
 
1980
;
20
:
24
48
.
93
Edwards
JE
Mesguer
F
Faura
CC
Moore
RA
McQuay
HJ
.
Single-dose dipyrone for acute postoperative pain
.
Cochrane Database Syst Rev
 
2001
;(
3
):
CD003227
.
94
Papadima
A
Lagoudianakis
EE
Antonakis
PT
et al
Parecoxib vs. lornoxicam in the treatment of postoperative pain after laparoscopic cholecystectomy: A prospective randomized placebo-controlled trial
.
Eur J Anaesthesiol
 
2007
;
24
:
154
8
.
95
Serner
M
Yilmazer
C
Yilmaz
I
et al
Patient-controlled analgesia with lornoxicam vs. Dipyrone for acute postoperative pain relief after septorhinoplasty: A prospective, randomized, double-blind, placebo-controlled study
.
Eur J Anaesthesiol
 
2008
;
25
:
177
82
.
96
Sharma
A
Pingle
A
Baliga
VP
.
Lornoxicam efficacy in acute pain (LEAP) trial
.
J Indian Med Assoc
 
2008
;
106
:
811
3
.
97
Salonen
A
Silvola
J
Kokki
H
.
Does 1 or 2 g paracetamol added to ketoprofen enhance analgesia in adult tonsillectomy patients?
Acta Anaesthesiol Scand
 
2009
;
53
:
1200
6
.
98
Korkmaz Dilmen
O
Tunali
Y
Cakmakkaya
OS
et al
Efficacy of intravenous paracetamol, metamizol and lornoxicam on postoperative pain and morphine consumption after lumbar disc surgery
.
Eur J Anaesthesiol
 
2010
;
27
:
428
32
.
99
Cheer
SM
Goa
KL
.
Parecoxib (parecoxib sodium)
.
Drugs
 
2001
;
61
:
1133
41
.
100
Karim
A
Laurent
A
Kuss
M
Hubbard
RC
Quian
J
.
Single dose tolerability and pharmacokinetics of parecoxib sodium, a COX-2 specific inhibitor following intramuscular administration [abstract]
.
Anesthesiology
 
2000
;
94
:
A944
.
101
Karim
A
Laurent
A
Kuss
ME
Qian
J
Hubbard
RC
.
Single dose tolerability and pharmacokinetics of parecoxib sodium, a COX-2 specific inhibitor following intravenous administration [abstract]
.
Anesthesiology
 
2000
;
94
:
A945
.
102
Karim
A
Laurent
A
Slater
ME
et al
A pharmacokinetic study of intramuscular (i.m.) parecoxib sodium in normal subjects
.
J Clin Pharmacol
 
2001
;
41
:
1111
9
.
103
Talley
JJ
Bertenshaw
SR
Brown
DL
et al
N-[[(5-methyl-3-phenylisoxazol yl) phenyl]sulfonyl]propanamide, sodium salt, parecoxib sodium: A potent and selective inhibitor of COX-2 for parenteral administration
.
J Med Chem
 
2000
;
43
:
1661
3
.
104
Soltesz
S
Gerbershagen
MU
Pantke
B
Eichler
F
Molter
G
.
Parecoxib versus dipyrone (metamizole) for postoperative pain relief after hysterectomy: A prospective, single-centre, randomized, double-blind trial
.
Clin Drug Investig
 
2008
;
28
:
421
8
.
105
Luscombe
KS
McDonnell
NJ
Muchatula
NA
Paech
MJ
Nathan
EA
.
A randomized comparison of parecoxib versus placebo for pain management following minor day stay gynaecological surgery
.
Anaesth Intensive Care
 
2010
;
38
:
141
8
.
106
Barton
SF
Langeland
FF
Snabes
MC
et al
Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparotomy surgery
.
Anesthesiology
 
2002
;
97
:
306
14
.
107
Rasmussen
GL
Steckner
K
Hogue
C
Torri
S
Hubbard
RC
.
Intravenous parecoxib sodium for acute pain after orthopedic knee surgery
.
Am J Orthop
 
2002
;
31
:
336
43
.
108
Daniels
SE
Grossman
EH
Kuss
ME
Talwalker
S
Hubbard
RC
.
Adouble-blind, randomized comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and placebo in a post-oral surgery pain model
.
Clin Ther
 
2001
;
23
:
1018
31
.
109
Noveck
RJ
Laurent
A
Kuss
M
Talwalker
S
Hubbard
RC
.
Parecoxib sodium does not impair platelet function in healthy elderly and non-elderly individuals
.
Clin Drug Invest
 
2001
;
21
:
465
76
.
110
Leese
PT
Talwalker
S
Kent
JD
Recker
DP
.
Valdecoxib does not impair platelet function
.
Am J Emerg Med
 
2002
;
20
:
275
81
.
111
Leese
PT
Recker
DP
Kent
JD
.
The COX-2 selective inhibitor, valdecoxib, does not impair platelet function in the elderly: Results of a randomized controlled trial
.
J Clin Pharmacol
 
2003
;
43
:
504
13
.
112
Sikes
DH
Agrawal
NM
Zhao
WW
et al
Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis
.
Eur J Gastroenterol Hepatol
 
2002
;
14
:
1101
11
.
113
Kivitz
A
Eisen
G
Zhao
WW
Bevirt
T
Recker
DP
.
Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis
.
J Fam Pract
 
2002
;
51
:
530
7
.
114
Harris
SI
Kuss
M
Hubbard
RC
Goldstein
JL
.
Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclooxygenase-2-specific inhibitor, compared with ketorolac, naproxen, and placebo
.
Clin Ther
 
2001
;
23
:
1422
8
.
115
Stoltz
RR
Harris
SI
Kuss
ME
et al
Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects
.
Am J Gastroenterol
 
2002
;
97
:
65
71
.
116
Lee
SY
Lee
WH
Lee
EH
Han
KC
Ko
YK
.
The effects of paracetamol, ketorolac, and paracetamol plus morphine on pain control after thyroidectomy
.
Korean J Pain
 
2010
;
23
:
124
30
.
117
Koppert
W
Frötsch
K
Huzurudin
N
et al
The effects of paracetamol and parecoxib on kidney function in elderly patients undergoing orthopedic surgery
.
Anesth Analg
 
2006
;
103
:
1170
6
.
118
Ng
A
Temple
A
Smith
G
Emembolu
J
.
Early analgesic effects of parecoxib versus ketorolac following laparoscopic sterilization: A randomized controlled trial
.
Br J Anaesth
 
2004
;
92
:
846
9
.
119
Leykin
Y
Casati
A
Rapotec
A
et al
A prospective, randomized, double-blind comparison between parecoxib and ketorolac for early postoperative analgesia following nasal surgery
.
Minerva Anestesiol
 
2008
;
74
:
475
9
.
120
Grundmann
U
Wörnle
C
Biedler
A
et al
The efficacy of the non-opioid analgesics parecoxib, paracetamol and metamizol for postoperative pain relief after lumbar microdiscectomy
.
Anesth Analg
 
2006
;
103
:
217
22
.
121
Kampe
S
Warm
M
Landwehr
S
et al
Clinical equivalence of IV paracetamol compared to IV dipyrone for postoperative analgesia after surgery for breast cancer
.
Curr Med Res Opin
 
2006
;
22
:
1949
54
.
122
Landwehr
S
Kiencke
P
Giesecke
T
et al
A comparison between IV paracetamol and IV metamizol for postoperative analgesia after retinal surgery
.
Curr Med Res Opin
 
2005
;
21
:
1569
75
.
123
Tiippana
E
Bachmann
M
Kalso
E
Pere
P
.
Effect of paracetamol and coxib with or without dexamethasone after laparoscopic cholecystectomy
.
Acta Anaesthesiol Scand
 
2008
;
52
:
673
80
.
124
Pierce
CA
Voss
B
.
Efficacy and safety of ibuprofen and acetaminophen in children and adults: A meta-analysis and qualitative review
.
Ann Pharmacother
 
2010
;
44
:
489
506
.
125
Ko
MJ
Lee
JH
Cheong
SH
et al
Comparison of the effects of acetaminophen to ketorolac when added to lidocaine for intravenous regional anesthesia
.
Korean J Anesthesiol
 
2010
;
58
:
357
61
.
126
Edwards
J
Meseguer
F
Faura
C
et al
Single dose dipyrone for acute postoperative pain
.
Cochrane Database Syst Rev
 
2010
;(
9
):
CD003227
.
127
Hyllested
M
Jones
S
Pedersen
JL
Kehlet
H
.
Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: A qualitative review
.
Br J Anaesth
 
2002
;
88
:
199
214
.
128
Ong
CK
Seymour
RA
Lirk
P
Merry
AF
.
Combining paracetamol (acetminophen) with nonsteroidal antiinflammatory drugs: A qualitative systematic review of analgesic efficacy for acute postoperative pain
.
Anesth Analg
 
2010
;
110
:
1170
9
.
129
Juhl
GI
Norholt
SE
Tonnesen
E
Hiesse-Provost
O
Jensen
TS
.
Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2 g starting dose following third molar surgery
.
Eur J Pain
 
2006
;
10
:
371
7
.
130
Würthwein
G
Koling
S
Reich
A
et al
Pharmacokinetics of intravenous paracetamol in children and adolescents under major surgery
.
Eur J Clin Pharmacol
 
2005
;
60
:
883
8
.
131
Allegaert
K
Rayyan
M
De Rijdt
T
Van Beek
F
Naulaers
G
.
Hepatic tolerance of repeated intravenous paracetamol administration in neonates
.
Pediatric Anesthesia
 
2008
;
18
:
388
92
.
132
Palmer
GM
Atkins
M
Anderson
BJ
et al
I.V. acetaminophen pharmacokinetics in neonates after multiple doses
.
Br J Anaesth
 
2008
;
101
:
523
30
.
133
Parra
D
Beckey
NP
Stevens
GR
.
The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy
.
Pharmacother
 
2007
;
27
:
675
83
.
134
Toes
MJ
Jones
AL
Prescott
L
.
Drug interactions with paracetamol
.
Am J Ther
 
2005
;
12
:
56
66
.
135
Rumack
BH
.
Acetaminophen hepatotoxicity: The first 35 years
.
J Toxicol Clin Toxicol
 
2002
;
40
:
3
20
.
136
Wootton
FT
Lee
WM
.
Acetaminophen hepatotoxicity in the alcoholic
.
South Med J
 
1990
;
83
:
1047
9
.
137
Whitcomb
DC
Block
GD
.
Association of acetaminophen hepatotoxicity with fasting and ethanol use
.
JAMA
 
1994
;
272
:
1845
50
.
138
Makin
AJ
Williams
R
.
Acetaminophen-induced hepatotoxicity: Predisposing factors and treatments
.
Adv Intern Med
 
1997
;
42
:
453
83
.
139
Kuffner
EK
Dart
RC
Bogdan
GM
et al
Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: A randomized, double-blind, placebo-controlled trial
.
Arch Intern Med
 
2001
;
161
:
2247
52
.
140
Larson
AM
Polson
J
Fontana
RJ
et al
Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study
.
Hepatology
 
2005
;
42
:
1364
72
.
141
Kuffner
EK
Green
JL
Bogdan
GM
et al
The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients—A multicenter randomized study
.
BMC Med
 
2007
;
5
:
13
.
142
Krotz
F
Schiele
TM
Klauss
V
Sohn
HY
.
Selective COX-2 inhibitors and risk of myocardial infarction
.
J Vasc Res
 
2005
;
42
:
312
24
.
143
Lesko
SM
Mitchell
AA
.
An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial
.
JAMA
 
1995
;
273
:
929
33
.
144
Lesko
SM
Mitchell
AA
.
Renal function after short-term ibuprofen use in infants and children
.
Pediatrics
 
1997
;
100
:
954
7
.
145
Houck
CS
Wilder
RT
McDermott
JS
Sethna
NF
Berde
CB
.
Safety of intravenous ketorolac therapy in children and cost savings with a unit dosing system
.
J Pediatr
 
1996
;
129
:
292
6
.
146
Lee
A
Cooper
MG
Craig
JC
Knight
JF
Keneally
JP
.
The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on postoperative renal function: A meta-analysis
.
Anaesth Intensive Care
 
1999
;
27
:
574
80
.
147
Miller
FC
Schorr
WJ
Lacher
JW
.
Zomepirac-induced renal failure
.
Arch Intern Med
 
1983
;
143
:
1171
3
.
148
Perazella
MA
Buller
GK
.
NSAID nephrotoxicity revisited: Acute renal failure due to parenteral ketorolac
.
South Med J
 
1993
;
86
:
1421
4
.
149
Quan
DJ
Kayser
SR
.
Ketorolac-induced acute renal failure following a single dose
.
J Toxicol Clin Toxicol
 
1994
;
32
:
305
9
.
150
Haragsim
L
Dalal
R
Bagga
H
Bastani
B
.
Ketorolac-induced acute renal failure and hyperkalemia: Report of three cases
.
Am J Kidney Dis
 
1994
;
24
:
578
80
.
151
Patel
NY
Landercasper
J
.
Ketorolac-induced postoperative acute renal failure: A case report
.
Wis Med J
 
1995
;
94
:
445
7
.
152
Sivarajan
M
Wasse
L
.
Perioperative acute renal failure associated with preoperative intake of ibuprofen
.
Anesthesiol
 
1997
;
86
:
1390
2
.
153
Feldman
HI
Kinman
JL
Berlin
JA
et al
Parenteral ketorolac: The risk for acute renal failure
.
Ann Intern Med
 
1997
;
126
:
193
9
.
154
Kovesi
TA
Swartz
R
MacDonald
N
.
Transient renal failure due to simultaneous ibuprofen and aminoglycoside therapy in children with cystic fibrosis
.
N Engl J Med
 
1998
;
338
:
65
6
.
155
Sheiner
PA
Mor
E
Chodoff
L
et al
Acute renal failure associated with the use of ibuprofen in two liver transplant recipients on FK506
.
Transplantation
 
1994
;
57
:
1132
3
.
156
Kehlet
H
Dahl
JB
.
Are perioperative nonsteroidal anti-inflammatory drugs ulcerogenic in the short term?
Drugs
 
1992
;
44
(
suppl 5
):
38
41
.
157
Forrest
JB
Heitlinger
EL
Revell
S
.
Ketorolac for postoperative pain management in children
.
Drug Saf
 
1997
;
16
:
309
29
.
158
McCann
KJ
Irish
J
.
Postoperative gastrointestinal bleeding: A case report involving a non-steroidal anti-inflammatory drug
.
J Can Dent Assoc
 
1994
;
60
:
124
8
.
159
Wolfe
PA
Polhamus
CD
Kubik
C
Robinson
AB
Clement
DJ
.
Giant duodenal ulcers associated with the postoperative use of ketorolac: Report of three cases
.
Am J Gastroenterol
 
1994
;
89
:
1110
1
.
160
Yarboro
TL
.
Intramuscular Toradol, gastrointestinal bleeding, and peptic ulcer perforation: A case report
.
J Natl Med Assoc
 
1995
;
87
:
225
7
.
161
Alcaraz
A
López-Herce
J
Seriñá
C
et al
Gastrointestinal bleeding following ketorolac administration in a pediatric patient
.
J Pediatr Gastroenterol Nutr
 
1996
;
23
:
479
81
.
162
Buchman
AL
Schwartz
MR
.
Colonic ulceration associated with the systemic use of nonsteroidal antiinflammatory medication
.
J Clin Gastroenterol
 
1996
;
22
:
224
6
.
163
Bombardier
C
Laine
L
Reicin
A
et al
VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis
.
N Engl J Med
 
2000
;
343
:
1520
8
.
164
Feldman
M
McMahon
AT
.
Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity?
Ann Intern Med
 
2000
;
132
:
134
43
.
165
Silverstein
FE
Faich
G
Goldstein
JL
et al
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study
.
JAMA
 
2000
;
284
:
1247
55
.
166
Dannhardt
G
Kiefer
W
.
Cyclooxygenase inhibitors–current status and future prospects
.
Eur J Med Chem
 
2001
;
36
:
109
26
.
167
Schug
SA
.
The role of COX-2 inhibitors in the treatment of postoperative pain
.
J Cardiovasc Pharmacol
 
2006
;
47
(
suppl 1
):
S82
6
.
168
Bresalier
RS
Sandler
RS
Quan
H
et al
Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial
.
N Engl J Med
 
2005
;
352
:
1092
102
.
169
Meagher
EA
.
Cardiovascular and renovascular implications of COX-2 inhibition
.
Curr Pharm Des
 
2004
;
10
:
603
11
.
170
Nussmeier
NA
Whelton
AA
Brown
MT
et al
Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery
.
N Engl J Med
 
2005
;
352
:
1081
91
.
171
Rimon
G
Sidhu
RS
Lauver
DA
et al
COXIBs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1
.
Proc Natl Acad Sci USA
 
2010
;
107
:
28
33
.
172
Munsterhjelm
E
Munsterhjelm
NM
Niemi
TT
et al
Dose-dependent inhibition of platelet function by acetaminophen in healthy volunteers
.
Anesthesiol
 
2005
;
103
:
712
7
.
173
Niemi
TT
Taxell
C
Rosenberg
PH
.
Comparison of the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers
.
Acta Anaesthesiol Scand
 
1997
;
41
:
1353
8
.
174
Silvanto
M
Munsterhjelm
E
Savolainen
S
et al
Effect of 3 g of intravenous paracetamol on post-operative analgesia, PLT function and liver enzymes in patients undergoing tonsillectomy under local anaesthesia
.
Acta Anaesthesiol Scand
 
2007
;
51
:
1147
54
.
175
Schafer
A
.
Effects of nonsteroidal anti-inflammatory drugs on platelet function and systemic hemostasis
.
J Clin Pharmacol
 
1995
;
35
:
209
19
.
176
Leese
PT
Hubbard
RC
Karim
A
et al
Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: A randomized, controlled trial
.
J Clin Pharmacol
 
2000
;
40
:
124
32
.
177
Gajraj
NM
.
Cyclooxygenase-2 inhibitors
.
Anesth Analg
 
2003
;
96
:
1720
38
.
178
Reuter
SH
Montgomery
WW
.
Aspirin vs acetaminophen after tonsillectomy. A comparative double-blind clinical study
.
Arch Otolarngol
 
1964
;
80
:
214
7
.
179
Connelly
CS
Panush
RS
.
Should nonsteroidal anti-inflammatory drugs be stopped before elective surgery?
Arch Intern Med
 
1991
;
151
:
1963
6
.
180
Robinson
CM
Christie
J
Malcom-Smith
N
.
Nonsteroidal antiinflammatory drugs, perioperative blood loss, and transfusion requirements in elective hip arthroplasty
.
J Arthroplasty
 
1993
;
8
:
607
10
.
181
Fauno
P
Petersen
KD
Husted
SE
.
Increased blood loss after preoperative NSAID: Retrospective study of 186 hip arthroplasties
.
Acta Orthop Scand
 
1993
;
64
:
522
4
.
182
Robinson
PM
Ahmed
I
.
Diclofenac and post-tonsillectomy haemorrhage
.
Clin Otolaryngol
 
1994
;
19
:
344
5
.
183
Gallagher
JE
Blauth
J
Fornadley
JA
.
Perioperative ketorolac tromethamine and postoperative hemorrhage in cases of tonsillectomy and adenoidectomy
.
Laryngoscope
 
1995
;
105
:
606
9
.
184
Rusy
LM
Houck
CS
Sullivan
LJ
et al
A double-blind evaluation of ketorolac tromethamine versus acetaminophen in pediatric tonsillectomy: Analgesia and bleeding
.
Anesth Analg
 
1995
;
80
:
226
9
.
185
Judkins
JH
Dray
TJ
Hubbell
RN
.
Intraoperative ketorolac and posttonsillectomy bleeding
.
Arch Otolarngol Head Neck Surg
 
1996
;
122
:
937
40
.
186
Splinter
WM
Rhine
EJ
Roberts
DW
Reid
CW
MacNeill
HB
.
Preoperative ketorolac increases bleeding after tonsillectomy in children
.
Can J Anaesth
 
1996
;
43
:
560
3
.
187
Harley
EH
Dattolo
RA
.
Ibuprofen for tonsillectomy pain in children: Efficacy and complications
.
Otolarngol Head Neck Surg
 
1998
;
119
:
492
6
.
188
Wierod
FS
Frandsen
NJ
Jacobsen
JD
Hartvigsen
A
Olsen
PR
.
Risk of hemorrhage from transurethral prostatectomy in acetylsalicylic acid and NSAID-treated patients
.
Scand J Urol Nephrol
 
1998
;
32
:
120
2
.
189
Agarwal
A
Gerson
CR
Seligman
I
Dsida
RM
.
Postoperative hemorrhage after tonsillectomy: Use of ketorolac tromethamine
.
Otolarngol Head Neck Surg
 
1999
;
120
:
335
9
.
190
Schmidt
A
Bjorkman
S
Akeson
J
.
Preoperative rectal diclofenac versus paracetamol for tonsillectomy: Effects on pain and blood loss
.
Acta Anaesthesiol Scand
 
2001
;
45
:
48
52
.
191
Marret
E
Flahault
A
Samama
C-M
Bonnet
F
.
Effects of postoperative, nonsteroidal, anti-inflammatory drugs on bleeding risk after tonsillectomy: Meta-analysis of randomized, controlled trials
.
Anesthesiology
 
2003
;
98
:
1497
502
.
192
Hong
Y
Gengo
FM
Rainka
MM
Bates
VE
Mager
DE
.
Population pharmacodynamic modeling of aspirin- and ibuprofen-induced inhibition of PLT aggregation in healthy subjects
.
Clin Pharmacother
 
2008
;
47
:
129
37
.
193
Munsterhjelm
E
Niemi
TT
Ylikorkala
O
Neuvonen
PJ
Rosenberg
PH
.
Influence on PLT aggregation of i.v. parecoxib and acetaminophen in healthy volunteers
.
Br J Anaesth
 
2006
;
97
:
226
31
.
194
Evans
AM
Nation
RL
Sansom
LN
Bochner
F
Somogyi
AA
.
Effect of racemic ibuprofen dose on the magnitude and duration of PLT cyclo-oxygenase inhibition: Relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen
.
Br J Clin Pharmacol
 
1991
;
31
:
131
8
.
195
Knijff-Dutmer
EAJ
Kalsbeek-Batenburg
EM
Koerts
J
van de Laar
MAFJ
.
Platelet function is inhibited by non-selective non-steroidal anti-inflammatory drugs but not by cyclo-oxygenase-2-selective inhibitors in patients with rheumatoid arthritis
.
Rheumatology
 
2002
;
41
:
458
61
.
196
Graff
J
Arabmotlagh
M
Cheung
R
Geisslinger
G
Harder
S
.
Effects of parecoxib and dipyrone on platelet aggregation in patients undergoing meniscectomy: A double-blind, randomized, parallel-group study
.
Clin Ther
 
2007
;
29
:
438
47
.
197
Bauer
KA
Gerson
W
Wright
C
et al
Platelet function following administration of a novel formulation of intravenous diclofenac sodium versus active comparators: A randomized, single dose, crossover study in healthy male volunteers
.
J Clin Anesth
 
2010
;
22
:
510
8
.
198
Macassey
EA
Baguley
C
Dawes
P
Gray
A
.
15-year audit of post-tonsillectomy haemorrhage at Dunedin Hospital
.
Anz J Surg
 
2007
;
77
:
579
82
.
199
Jin
F
Chung
F
.
Multimodal analgesia for postoperative pain control
.
J Clin Anesth
 
2001
;
13
:
524
39
.
200
ASA-2004: ASA Task Force
.
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
 
2004
;
100
:
1573
81
.
201
White
PF
Kehlet
H
Neal
JM
et al
Fast-Track Surgery Study Group. The role of the anesthesiologist in fast-track surgery: From multimodal analgesia to perioperative medical care
.
Anesth Analg
 
2007
;
104
:
1380
96
.
202
Kehlet
H
.
Multimodal approach to postoperative recovery
.
Curr Opin Crit Care
 
2009
;
15
:
355
8
.