The role of Intravenous Acetaminophen in acute pain management — I A Case-Illustrated Review

For more than a century, acetaminophen (N-acetyl-p-aminophenol; known internationally as paracetamol) has been recognized worldwide as a safe and effective agent for relieving pain and reducing fever in a wide range of patients. Synthesized in 1878 and first used clinically in 1887, the drug was not widely marketed in the United States (U.S.) until the 1950s. It has since become one of the mostly widely used analgesic and antipyretic agents and is often the first-line therapy of choice for children. Outside the U.S., intravenous (IV) acetaminophen has been available since 2001 in Europe under the trade name Perfalgan (Bristol-Myers Squibb, Anagni, Italy) and is now available in approximately 80 countries. Until recently, acetaminophen was available in the U.S. only in oral and rectal suppository formulations. However, oral and rectal acetaminophen formulations are associated with a slower onset of action and more variable analgesic activity than IV acetaminophen, making them less useful in perioperative, postoperative, and acute care settings. In November 2010, the U.S. Food and Drug Administration (FDA) approved Ofirmev (acetaminophen for injection; Cadence Pharmaceuticals; San Diego, CA) for: 1) the management of mild to moderate pain; 2) the management of moderate to severe pain with adjunctive opioid analgesics; and 3) the reduction of fever in adults and children (age ?2 years). The present case-illustrated review of IV acetaminophen begins with a discussion of the rationale for the drug's development and proceeds to analyze the clinical pharmacology, efficacy, safety, and nursing implications of its use, both as monotherapy and in combination with other agents as part of a multimodal pain therapy strategy. The Need for Improved Acute Pain Management Effective treatment for pain is essential to achieve and maintain patient comfort and good clinical outcomes. Inadequate acute pain management can result in shortened or missed rehabilitation sessions and delayed mobilization, and delayed ambulation can increase the risk for venous thromboembolism. The psychologic effects of uncontrolled pain, such as insomnia, depression, and anxiety, may contribute to decreased quality of life, poor patient outcomes, and decreased patient satisfaction. Ineffective pain management also results in increased health care costs. In one study of patients undergoing surgical repair of a hip fracture, patients with higher postoperative pain scores had significantly longer hospital stays. Another study found that the primary reason for unanticipated postoperative hospital admissions or readmissions was not due to surgical complications, medical complications, or bleeding, but was due to poorly controlled pain. Despite improvements in analgesic delivery, including new analgesic options and the use of patient-controlled analgesia (PCA) by a variety of routes of administration, postoperative pain remains undertreated. The continued undertreatment of acute pain worldwide led the International Association for the Study of Pain (IASP) to designate 2011 as the Global Year Against Acute Pain. A comparison of two studies investigating the epidemiology of acute pain in postoperative patients-one conducted in 1995 and another in 2003-illustrates that pain control did not improve during that period. Warfield and Kahn (1995) reported the results of a study using telephone surveys of patients who had undergone surgery in teaching or community hospitals. They found that ~77% of patients reported experiencing postsurgical pain, and 80% of those patients rated their postsurgical pain as moderate to extreme. Apfelbaum, Chen, Mehta, & Gan (2003) reported similar results from their study using telephone surveys of 250 adults who had had recent surgical procedures. They found that ~80% of patients reported having acute postsurgical pain, and 86% of those patients reported that the pain was moderate, severe, or extreme. Undertreatment of acute postoperative pain also increases the risk of progression from acute to chronic (persistent) pain. Kehlet, Jensen, and Woolf (2006) examined the incidence of persistent pain after common surgical procedures, such as coronary artery bypass surgery, breast and thoracic surgery, groin hernia repair, and leg amputation, and found that chronic (often disabling) pain can persist for months or years after the surgical wound has healed. Disadvantages of Opioid Monotherapy Opioids have been used as analgesics for more than 2,000 years and continue to be a key element in moderate to severe acute postoperative pain management. However, opioid-only treatment plans can result in intolerable and dangerous adverse effects, including constipation, nausea and vomiting, excessive sedation, and respiratory depression. Concerns are also being raised about a possible link between opioid-only treatment plans and a paradoxic clinical situation in which increasing doses of opioid result in increasing sensitivity to pain, a condition referred to as opioid-induced hyperalgesia. Adverse effects associated with opioids commonly occur and can prevent patients from experiencing satisfactory analgesia. In a systematic review analyzing opioid-induced adverse effects among postoperative patients in 45 randomized-controlled studies, 31% of patients experienced an adverse gastrointestinal (GI) event (ileus, nausea, vomiting, constipation), 30.3% of patients reported an adverse central nervous system (CNS) event (somnolence, sedation), 18.3% of patients reported pruritus, 17.5% of patients experienced urinary retention, and 2.8% of patients had respiratory depression. These adverse effects, especially nausea and vomiting, can be so unpleasant that some patients are willing to accept less-than-adequate pain relief to avoid them. CNS effects associated with opioids also increase the risk for major postoperative complications, such as aspiration, respiratory failure, decreased mobility, and falls. Multimodal Pain Management To address the undertreatment of postoperative pain and the limitations of opioid monotherapy, a strategy known as multimodal pain management was introduced in the early 1990s. This approach simultaneously administers two or more analgesic agents with different mechanisms of action. Combination therapy using drugs with distinct mechanisms of action may add analgesia or have a synergistic effect and allow for better analgesia with the use of lower doses of a given medication than if the drug were used alone. For example, postoperative multimodal analgesia may consist of the use of opioid and nonopioid pharmacologic agents, as well as regional anesthesia and continuous peripheral neural blockade. The multimodal approach has been endorsed by many professional organizations, including the American Society of Anesthesiologists (ASA) (ASA Task Force, 2012), the American Pain Society (APS) (APS, 2008), and the American Society for Pain Management Nursing (ASPMN). The ASA acute pain management practice guidelines state that clinicians should use multimodal analgesia whenever possible in the perioperative setting. The ASA recommends that all surgical patients receive an around-the-clock (ATC) regimen of acetaminophen and a nonsteroidal antiinflammatory drug (NSAID) unless contraindicated, and that the dosages and duration of therapy should be individualized, balancing efficacy with the risk of adverse events. In addition, regional anesthesia should be considered (ASA Task Force, 2012). Numerous studies have shown this type of multimodal treatment plan can produce a significant opioid dose-sparing effect. Most recently, anticonvulsants, such as gabapentin and pregabalin, have also been added to postoperative pain treatment plans in an attempt to produce a dose-sparing effect and to prevent persistent postsurgical pain syndromes. In addition to reducing opioid consumption and minimizing the incidence of opioid-related adverse events, a multimodal approach can improve postoperative pain relief, increase patient satisfaction, expedite mobilization and rehabilitation, and reduce health care costs. The ASPMN guidelines on monitoring for opioid-induced sedation and respiratory depression state that nurses should advocate for opioid-sparing pain management strategies before, during, and after surgery. The ASPMN guidelines also appropriately point out that, despite the evidence that multimodal pain management plans may have opioid dose-sparing effects, sedation and respiratory status must still be carefully monitored when opioid analgesics are given concomitantly with nonopioids. One multimodal strategy for the management of postoperative pain involves a stepwise approach. In this approach, for mild postoperative pain, nonopioid analgesics (acetaminophen and an NSAID) are administered in a scheduled ATC dosing regimen along with local anesthetic infiltration of the surgical site before the incision is made. Then, analgesics with different modes of action are added in subsequent steps based on increased or anticipated increased pain intensity. For moderate postoperative pain, in addition to the nonopioid analgesics, an opioid analgesic may be administered on an as-needed basis for breakthrough pain. For continuous severe pain, a modified-release opioid may be administered ATC or a continuous local anesthetic peripheral nerve blockade might be added. The rationale for this strategy is based on the known additive or synergistic effects between different classes of analgesics, which allow a reduction in any one individual drug dose, thus potentially lowering the incidence of that medication's adverse effects. Delivery of Analgesics Opioids are available for delivery by a number of different routes, including oral, rectal, IV, subcutaneous, transdermal, intraspinal, transmucosal, intranasal, and topical. Commonly used oral opioids include hydrocodone and oxycodone. In the U.S., a number of oral nonopioid analgesics, including acetaminophen, nonselective NSAIDs, such as naproxen (Naprosyn) and ibuprofen (Advil, Motrin), and the COX-2-selective NSAID celecoxib (Celebrex), are approved and frequently used for acute pain treatment, either as monotherapy or in combination with opioids. NSAIDs are considered to be appropriate for mild- to some moderate-intensity acute pain and as adjuncts to opioids for the relief of more severe acute pain. They do not produce respiratory depression or impair GI motility so are considered an important component with acetaminophen in a multimodal treatment plan for acute pain. However, the use of NSAIDs may be limited in some patients, and an understanding of their underlying mechanisms of action is important to ensuring their safe use. NSAIDs exert their analgesic and antiinflammatory effects by blocking the production of prostaglandins, which are compounds that facilitate the transmission of pain following tissue damage (e.g., surgical incision). Prostaglandins are Continued on page 44 Continued from page 26 formed when the enzyme phospholipase breaks down phospholipids into arachidonic acid. In turn, the enzyme cyclooxygenase (COX) breaks down arachidonic acid. Cyclooxygenase is a small family of enzymes, each of which is known as an isoenzyme. The best characterized isoenzymes are COX-1 and COX-2. COX-1 mediates primarily beneficial processes and is present in practically all tissues. COX-2 is found mainly at sites of injury and in the brain and mediates harmful processes. Nonselective NSAIDS, such as naproxen, ibuprofen, and ketorolac (Toradol), inhibit both COX-1 and COX-2. COX-2 selective NSAIDs, such as celecoxib, inhibit just COX-2. The analgesia and antiinflammatory effects induced by NSAIDs are the result of COX-2 inhibition, while the adverse effects of NSAIDs are generally the result of COX-1 inhibition. For example, an adverse effect of COX-1 inhibition is reduced platelet aggregation, which helps to explain why many surgeons tell their patients to withhold nonselective NSAIDs before surgery to avoid excessive incisional site bleeding. The most common adverse effect of NSAIDs is gastric toxicity, and older adults and individuals with a history of peptic ulcer disease are among the highest risk for this adverse effect. NSAIDs can also induce acute renal failure, particularly in patients with acute or chronic volume depletion, cardiac failure, liver cirrhosis, ascites, diabetes, or preexisting hypertension. Shortly after the release of the COX-2-selective NSAIDs (e.g., rofecoxib [Vioxx] and valdecoxib [Bextra]), research revealed an association between their perioperative use and an increase in renal dysfunction and adverse cardiovascular events, such as myocardial infarction and stroke, in patients who had undergone high-risk cardiac surgery. The underlying mechanism for this is not entirely clear. All NSAIDs now carry boxed warnings for both cardiovascular and GI adverse effects. Oral analgesics have a relatively slow onset of action due to the time required to absorb the medication from the GI tract. In addition, many hospitalized patients may not be able to take oral medications owing to nothing-by-mouth status, nausea and vomiting, reduced GI motility or function, endotracheal intubation, or the effects of anesthesia and sedation. The enteral route may also be compromised by the nature of the surgery, thereby precluding oral drug administration. The use of an analgesic in an IV formulation during the immediate postoperative period provides a number of advantages, including improved bioavailability and earlier onset of action compared with oral and rectal formulations. Most of the first-line opioids are available in IV formulation; however, until recently, the only nonopioid IV analgesics approved for use in the U.S. were in the NSAID family: ketorolac and ibuprofen (Caldolor). Ketorolac is a generic drug available in the U.S. from a number of manufacturers. Intravenous ibuprofen was approved by the FDA in mid-2009 for the management of mild to moderate pain, management of moderate to severe pain as an adjunct to opioid analgesics, and reduction of fever. Neither of these IV NSAIDs is currently FDA approved for use in pediatric patients. IV Acetaminophen Intravenous acetaminophen differs in many ways from the available IV opioids and NSAIDs. It is the only approved IV nonopioid analgesic that does not include a boxed warning on the label and that is indicated for use in pediatric patients. The drug is not associated with the increased incidence of nausea, vomiting, and respiratory depression that can occur with opioids, or the platelet dysfunction, gastritis, and renal toxicity that are sometimes associated with NSAIDs. Intravenous acetaminophen has a faster onset and results in more predictable pharmacokinetics than oral or rectal acetaminophen formulations. In a recent study, in which six adult volunteers were given IV, oral, or rectal acetaminophen, the mean IV Cmax (maximum plasma concentration of drug) was nearly twice that observed with oral administration and nearly four times that observed with rectal administration. The IV group showed consistently earlier and higher peak plasma and cerebrospinal fluid (CSF) maximum concentration values than after either oral or rectal delivery. The variability in plasma and CSF results was much higher in the oral and rectal groups than in the group that received IV acetaminophen. A major benefit is that IV acetaminophen may be administered before or during surgery, permitting the initiation of effective analgesic therapy in the early phase of the postoperative period. When patients are able to tolerate oral intake, they may be switched from IV to oral acetaminophen to maintain the predictable analgesia established by the IV route. Intravenous acetaminophen appears to avoid first-pass hepatic exposure and metabolism via portal circulation, which may reduce the potential for hepatic injury. With therapeutic dosing (up to 4,000 mg daily), IV acetaminophen is rarely associated with hepatotoxicity, and it has been shown to be safe for use in some patients with underlying liver conditions. Nonetheless, according to its prescribing information, IV acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease. Because of its efficacy, safety, lack of clinically significant drug interactions, and lack of the adverse effects associated with other analgesics, IV acetaminophen is an attractive component of a multimodal analgesic treatment plan. Clinical Pharmacology Mechanism of Action: Acetaminophen has both analgesic and antipyretic effects. Although the exact mechanisms of action of acetaminophen are still unclear, it is thought to exert its analgesic activity by inhibiting the synthesis of prostaglandins in the CNS (central acting) and peripherally blocking pain impulse generation. Unlike NSAIDs, acetaminophen is not a peripheral COX inhibitor. In addition, it has been proposed that acetaminophen has a serotonergic (5-HT) mechanism and a cannabinoid agonism mechanism, which may contribute to its analgesic effect. The antipyretic effect of acetaminophen is thought to involve inhibition of the hypothalamic heat-regulating center, prostaglandin inhibition, and cannabinoid agonism. The differences in mechanisms of action between acetaminophen and NSAIDs are likely responsible not only for the synergistic effect they have when used in combination, but also for the differences in safety profiles observed with the drugs. Pharmacokinetics and Pharmacodynamics: The pharmacokinetics of IV acetaminophen has been studied in patients and healthy volunteers in a wide range of ages, from premature neonates to adults 60 years old. IV acetaminophen achieves a higher Cmax and an earlier time to maximum concentration (Tmax), with less intrasubject variability than bioequivalent oral or rectal formulations. A major advantage of IV acetaminophen is that the median time to reach Tmax for IV acetaminophen is much faster than typically reported for oral or rectal formulations (>45 minutes). Cmax, which occurs at the end of the 15-minute infusion of IV acetaminophen, is up to 70% higher than that observed with the same dose of oral acetaminophen, although the overall exposure (area under the concentration time curve) is very similar. The higher Cmax with IV acetaminophen compared with oral acetaminophen does not seem to compromise the drug's safety profile, because the Cmax at this dose remains far below the 150 mg/L concentration considered to be the threshold for potential hepatotoxicity. Acetaminophen is detectable in the CSF within minutes after IV administration. The rapid CSF penetration and earlier and higher Cmaxobserved with IV acetaminophen seem to be responsible for its more rapid onset and peak efficacy compared with oral or rectal acetaminophen. The drug's duration of effect is predictable, from 4 to 6 hours. Metabolism: Acetaminophen undergoes metabolism by the liver via three pathways: 1) conjugation with glucuronide; 2) conjugation with sulfate; and 3) oxidation via the cytochrome P450 enzyme pathway (primarily CYP2E1). When delivered orally, acetaminophen undergoes first-pass metabolism in the liver; however, IV administration bypasses first-pass liver metabolism. Compared with the oral route, the IV route of administration reduces initial hepatic acetaminophen exposure by approximately twofold. Dosing and Administration Intravenous acetaminophen may be given as a single dose or as repeated doses. The maximum daily dose of acetaminophen is based on all routes of administration (i.e., IV, oral, and rectal) and all products (prescription and nonprescription) containing acetaminophen. It is not necessary to adjust the dose when converting between oral and IV acetaminophen in adults and adolescents. Intravenous acetaminophen is supplied in a 100-mL glass vial containing 1,000 mg (10 mg/mL) ready-to-use acetaminophen (i.e., no reconstitution or dilution is required). The entire dose of IV acetaminophen is administered over 15 minutes, and the infusion must be vented for proper delivery. Patients who weigh <50 kg should not receive the entire 100-mL vial of IV acetaminophen. Therefore, to avoid the inadvertent delivery of the total volume of the vial to these patients, the appropriate dose must be aseptically withdrawn and placed into a separate empty sterile container (e.g., glass bottle, plastic IV container, or syringe) before administration. Once the vacuum seal of the glass vial has been penetrated, the dose of IV acetaminophen must be administered within 6 hours. IV acetaminophen is a single-use vial, and the unused portion must be discarded. Other medications should not be added to the IV acetaminophen solution. Diazepam and chlorpromazine hydrochloride are physically incompatible with IV acetaminophen, so simultaneous IV administration of these drugs should be avoided. To prevent the possibility of an air embolism, it is important to observe the end of the infusion. Clinical Research on the Use of IV Acetaminophen Preemptive Analgesia: An IV formulation of acetaminophen may have important implications for implementation of a preemptive approach to the management of postoperative pain (i.e., dosing an analgesic before a pain stimulus, such as a surgical incision, with the intent to reduce subsequent pain), a concept introduced in the clinical setting decades ago. One goal of preemptive analgesia is to decrease pain by timing the analgesic's peak pharmacodynamic effect with the anticipated onset of pain or peak pain response. Two studies demonstrated a preemptive effect with the administration of IV acetaminophen before surgical incision. In one of these studies, 82 patients undergoing total abdominal hysterectomy were randomized to receive either 1,000 mg IV acetaminophen preemptively 30 minutes before anesthesia induction (group 1; n = 28), 1,000 mg IV acetaminophen at the end of surgery before skin closure (group 2; n = 27), or placebo (group 3; n = 27). No statistically significant differences were found between the operation times among the three groups (group 1, 121.6 min; group 2, 114.3 min; group 3, 118.3 min). Postoperatively, all patients received IV PCA morphine rescue as needed. Total morphine consumption in both IV acetaminophen groups (group 1, 25.93 mg; group 2, 35.73 mg; p < .05 for both) was significantly lower than in the placebo group (62.93 mg), and the preinduction acetaminophen group used less morphine than the end-of-surgery acetaminophen group (p < .05). Another important finding was that, compared with both IV acetaminophen groups, the placebo group had a statistically significantly higher incidence of postoperative nausea, vomiting, and itching (p < .05 for each). Patients in group 1 experienced the lowest incidences of all of these adverse effects and the shortest length of hospital stay (group 1, 5.03 days; group 2, 5.20 days; group 3, 6.43 days). In the second study of preemptive analgesia, 80 patients undergoing cesarean section were randomized to receive either 1,000 mg IV acetaminophen plus 75 mg intramuscular (IM) diclofenac preemptively before surgical incision but after induction of anesthesia (n = 40) or 1,000 mg IV acetaminophen plus 75 mg IM diclofenac at the end of surgery before skin closure (n = 40). The exact time of analgesic administration was not reported, although the authors mentioned consideration of a 45-minute peak time for IM diclofenac. All patients were given 3 ?g/kg IV fentanyl immediately after delivery, and postoperatively, all patients could receive as-needed rescue opioid analgesia (opioid was not named in the report). The need for rescue analgesia for treatment of breakthrough pain was recorded during cleaning after surgery, transfer from the operating room table to the stretcher, and during transport from the operating room to the PACU. Patients in the group receiving the study treatment before surgery reported significantly fewer total instances of breakthrough pain compared with patients in the group receiving study treatment at the end of surgery (45 vs. 90; p < .001). In the group receiving study treatment before surgery, seven patients required rescue opioid before transfer to the PACU and 14 patients required rescue opioid during transfer. In the group receiving study treatment at the end of surgery, 14 patients required rescue opioid before transfer to the PACU and the balance of patients (26) required rescue opioid immediately in the PACU. No other patient outcomes were reported. To be continued...