The Role of Intravenous Acetaminophen in Acute Pain Management

A Case-Illustrated Review

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


Pain Manag Nurs. 2012;13(2):107-124. 

In This Article

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 (Kehlet & Dahl, 1993; White, 2008). 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 (Pasero 2011). 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) (Jarzyna et al., 2011).

The ASA acute pain management practice guidelines state that clinicians should use multimodal analgesia whenever possible in the perioperative setting (ASA Task Force, 2012). 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 (ASA Task Force, 2012; Pasero et al., 2011). 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 (Pasero, 2011; Pasero, Polomano, Portenoy, & McCaffery, 2011). 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 (Buvanendran & Kroin, 2009; White et al., 2007).

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 (Jarzyna et al., 2011). 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 (Jarzyna et al., 2011).

One multimodal strategy for the management of postoperative pain involves a stepwise approach (Table 1). 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 (Crews, 2002). 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 (White, 2008).

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 (Pasero et al., 2011). 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 (Pasero, Portenoy, & McCaffery, 2011). 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 (Pasero, Portenoy, & McCaffery, 2011). 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) (Pasero & Portenoy, 2011). Prostaglandins are 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 (Pasero & Portenoy, 2011). 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 (Pasero, Portenoy, & McCaffery, 2011). 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 (Nussmeier Whelton, Brown, Langford, Hoeft, Parlow, … Verburg, 2005; Ott, Nussmeier, Duke, Feneck, Alston, Snabes, … Multicenter Study of Perioperative Ischemia Research Group, Ischemia Research and Education Foundation Investigators, 2003). The underlying mechanism for this is not entirely clear (Pasero, Portenoy, & McCaffery, 2011). All NSAIDs now carry boxed warnings for both cardiovascular and GI adverse effects (Cumberland, 2009; U.S. Food and Drug Administration, 2005).

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 (Pasero et al., 2011). The enteral route may also be compromised by the nature of the surgery, thereby precluding oral drug administration (Joshi & Ogunnaike, 2005; White, 2008).

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 (Holmér Pettersson, Jakobsson, & Owall, 2006; Malaise et al., 2007). 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 (Cumberland, 2009). Neither of these IV NSAIDs is currently FDA approved for use in pediatric patients.


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