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.

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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Next Section

Abstract and Introduction
The Need for Improved Acute Pain Management
Multimodal Pain Management
IV Acetaminophen
Conclusion and Nursing Implications
References
Sidebar

Table 1. Stepwise Multimodal Pain Therapy
Step 1	Mild postoperative pain	Nonopioid analgesics (acetaminophen, NSAID) and Local anesthetic infiltration
Step 2	Moderate postoperative pain	Nonopioid analgesics (acetaminophen, NSAID) and Local anesthetic infiltration and Intermittent doses of opioid analgesics
Step 3	Severe postoperative pain	Nonopioid analgesics (acetaminophen and NSAID) and Local anesthetic infiltration and Intermittent doses of opioid analgesics for breakthrough pain and Local anesthetic peripheral nerve block (with or without catheter) for continuous severe pain or Modified-release opioid analgesics for continuous pain

Modified from: Crews, J. C. (2002). Multimodal pain management strategies for office-based and ambulatory procedures.

Table 2. Dosing for IV Acetaminophen
Age Group	Dose Given Every 4 Hours	Dose Given Every 6 Hours	Maximum Single Dose	Maximum Total Daily Dose of Acetaminophen (by Any Route)
Adults and adolescents (≥13 years old) weighing ≥50 kg	650 mg	1,000 mg	1,000 mg	4,000 mg in 24 hours
Adults and adolescents (≥13 years old) weighing <50 kg	12.5 mg/kg	15 mg/kg	15 mg/kg (up to 750 mg)	75 mg/kg in 24 hours (up to 3,750 mg)
Children ≥2 to 12 years old	12.5 mg/kg	15 mg/kg	15 mg/kg	75 mg/kg

Reference: Cadence, 2010.

Table 3. Clinical Studies of Postsurgical IV Acetaminophen in Adult Patients
Authors/Year Published	Surgical Procedure	No. of Patients	Comparators	Results
Sinatra et al., 2005	Total hip or knee arthroplasty	101	•IV acetaminophen (1,000 mg) •Placebo	•IV acetaminophen plus PCA morphine improved pain relief compared with placebo plus PCA morphine over 24 hours •IV acetaminophen reduced morphine consumption •Duration of analgesia (time to first rescue medication) was longer with IV acetaminophen •Patients' global evaluations of satisfaction were higher with IV acetaminophen
Wininger et al., 2010	Abdominal laparoscopic surgery	244	•IV acetaminophen (1,000 mg) •Placebo	IV acetaminophen produced greater reduction in pain intensity over 24 hours
Memis et al., 2010	Major abdominal or pelvic surgery	40	•IV acetaminophen (1,000 mg) •Placebo	•Postoperative meperidine consumption was significantly less with IV acetaminophen •Time to extubation was ~3 hours shorter for the IV acetaminophen group •Postoperative nausea and vomiting and sedation scores were significantly lower with IV acetaminophen
Atef & Fawaz, 2008	Tonsillectomy	76	•IV acetaminophen (1,000 mg) •Placebo	•Postoperative meperidine consumption was lower with IV acetaminophen (18 mg) than with placebo (82 mg) •Patients in the IV acetaminophen group experienced significantly less pain •The occurrence of insufficient pain relief was less with IV acetaminophen •No significant difference between groups in the incidence of adverse effects
Moller et al., 2005	Third molar extraction	101	•IV acetaminophen (1,000 mg) •Placebo	•IV acetaminophen provided significantly more effective pain relief than placebo •Duration of analgesia was longer with IV acetaminophen •Patients' global satisfaction was higher with IV acetaminophen
Juhl et al., 2006	Third molar extraction	297	•IV acetaminophen (1,000 mg) •IV acetaminophen (2,000 mg) •Placebo	•Pain relief and duration of analgesia with the 2,000 mg dose were improved compared with those seen with either the recommended 1,000 mg dose or placebo •No difference in adverse effects between the groups

Table 4. Clinical Studies of Peri- and Postsurgical IV Acetaminophen in Pediatric Patients
Authors/Year Published	Surgical Procedure	No. of Patients/Ages	Comparators	Results
Murat et al., 2005	Inguinal hernia repair	183 (1–12 y)	•IV acetaminophen (15 mg/kg) •Propacetamol (prodrug of acetaminophen; 30 mg/kg)	•Both treatments rapidly reduced pain scores, with a steep reduction from baseline pain intensity during the first 15-minute interval after infusion •The duration of analgesia (time to first rescue) was >4 hours for both groups •20% of patients in both groups required rescue medication •Global evaluations of "excellent" were reported for 76% of patients receiving IV acetaminophen
Alhashemi & Daghistani, 2006	Tonsillectomy	80 (3–16 y)	•IV acetaminophen (15 mg/kg) •IM meperidine (1 mg/kg)	Compared with IM meperidine, IV acetaminophen provided adequate analgesia, less sedation, and earlier readiness for PACU discharge
Alhashemi & Daghistani, 2007	Dental restoration	50 (3–16 y)	•IV acetaminophen (15 mg/kg) •IM meperidine (1 mg/kg)	Compared with IM meperidine, intraoperative IV acetaminophen resulted in slightly higher pain scores but earlier readiness for PACU discharge
Capici et al., 2008	Adenotonsillectomy	50 (2–5 y)	•IV acetaminophen (15 mg/kg) •Rectal acetaminophen (40 mg/kg)	Duration of analgesia (time to first rescue analgesia) was longer with rectal acetaminophen compared with IV acetaminophen

Table 5. Treatment-Emergent Adverse Reactions Occurring in ≥3% of Adult Patients Treated with IV Acetaminophen
System Organ Class (Preferred Term)	n (%)
System Organ Class (Preferred Term)	IV Acetaminophen (n = 402)	Placebo (n = 379)
Gastrointestinal disorders
Nausea	138 (34%)	119 (31%)
Vomiting	62 (15%)	42 (11%)
General disorders and administration site conditions
Pyrexia*	22 (5%)	52 (14%)
Nervous system disorders
Headache	39 (10%)	33 (9%)
Psychiatric disorders
Insomnia	30 (7%)	21 (5%)

Reference: Cadence, 2010.
*The pyrexia adverse reaction frequency data are included to point out that the antipyretic effects of IV acetaminophen may mask fever.

Sidebar

Case #1

Jill F. is a 51-year-old high school science teacher with stage IIIA breast cancer who underwent a mastectomy of her left breast 4 months ago. The adjacent lymph nodes and chest muscles were left intact. Her postoperative pain was managed with an opioid-only treatment plan (PRN ["as needed"] boluses IV morphine), and she experienced severe pain for most of the first 48 hours after surgery. At the 6-month postoperative visit with her nurse practitioner, she reports persistent, disabling postoperative pain ("continuous burning, tingling, like an electrical shock"). She is unable to return to work full time and participate in her usual social activities.

Case #2

Peter C. is a 48-year-old businessman who underwent a laparoscopic cholecystectomy as an outpatient. He was given a total of 150 μg IV fentanyl in 25 μg doses every 10–15 minutes for severe pain in the postanesthesia care unit (PACU). His pain was reduced to moderate intensity, but he experienced intractable nausea and excessive sedation necessitating admission for an overnight stay until the adverse effects resolved.

Case #3

Josephine B. is a 72-year-old retired secretary who is 6 hours after abdominal hysterectomy. Her pain treatment plan includes oral acetaminophen given preoperatively and continued every 6 hours postoperatively; IV ketorolac, initiated on admission to the PACU and continued every 6 hours; and IV PCA hydromorphone. She is resting comfortably with pain ratings of ≤4, and her sedation levels and respiratory status, checked hourly, have been satisfactory since admission to the clinical unit.

Case #4

Jim C. is a 49-year-old architect who will undergo rectal abscess repair. The surgeon anticipates that Jim's postoperative pain will be mild to moderate in intensity and instructs Jim to take 650 mg oral acetaminophen and 200 mg celecoxib with sips of water 2 hours before surgery. The surgeon infiltrates the surgical site with the long-acting local anesthetic bupivacaine (Marcaine) before incision. On admission to the PACU, Jim rates his pain as 5 on a scale of 0 to 10. He is given 50 μg IV fentanyl twice to reduce his pain to 2. He is discharged home 45 minutes after the last dose of fentanyl with instructions to take 650 mg acetaminophen every 6 hours and 200 mg celecoxib daily. He may also take 5–10 mg oxycodone every 4 hours as needed for moderate breakthrough pain.

Case #5

Jane R., a 37-year-old woman, is given IV acetaminophen in the preoperative holding area 10 minutes before undergoing a laparascopic tubal ligation. In the PACU after surgery, her pain rating is 4 on a scale of 0 to 10 and she is given 0.3 mg IV hydromorphone. She will be discharged home with orders to take 550 mg naproxen every 12 hours and 1,000 mg oral acetaminophen every 6 hours starting 6 hours after the preoperative IV acetaminophen dose.

Case #6

Mark J. is a 47-year-old man with a body mass index of 35 kg/m² who will undergo a laparascopic gastric bypass and enteral bypass. His surgeon uses a fast-track protocol that focuses on prevention of pain, early discharge, and active participation in important recovery activities, such as ambulation. Mark is given 1,000 mg IV acetaminophen before surgery, bupivacaine infiltration in the surgical site before incision, and 800 mg IV ibuprofen during surgery. He experiences excellent pain control with continued doses of IV acetaminophen and IV ibuprofen for the first 24 hours after surgery. He is moved to oral formulations of the nonopioid drugs before discharge on postoperative day 2.

Case #7

Thomas D. is 82 years old and has undergone an open colon resection and colostomy placement. His pain management plan includes continuous epidural infusion of hydromorphone and ropivacaine (Naropin) initiated preoperatively and a dose of 1,000 mg IV acetaminophen intraoperatively. 1,000 mg IV acetaminophen is given every 6 hours and the epidural infusion is continued postoperatively until Thomas is able to move to oral medications.

Case #8

Tyler C. is a 6-year-old boy who presents in the emergency room with right ulnar fracture. He rates his pain as 8 on the 0–10 Wong-Baker FACES scale. Two doses of IV morphine (0.05 mg/kg), given 10 minutes apart, in addition to IV acetaminophen (15 mg/kg) by 15-minute infusion reduced Tyler's pain to 4 within 30 minutes of admission.

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