Introduction

Postoperative pain management remains a significant challenge. Acetaminophen, a commonly used analgesic, is often administered in the perioperative period to manage acute pain. Its mechanism of action involves reversible inhibition of cyclooxygenase (COX), primarily in the central nervous system (CNS) as it is inactivated peripherally, resulting in analgesic and antipyretic effects without the anti-inflammatory properties seen with nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. It may also enhance analgesia by stimulating descending serotonin pathways that inhibit nociceptive signal transmission in the spinal cord, and by interfering with the delivery of peripheral β-endorphins to their receptors [2].

The manufacturer of IV acetaminophen, Ofirmev®, recommends a maximum daily dose of 4 g per day for adults and children ≥ 13 years of age and weighing ≥ 50 kg. However, they advise not exceeding 1 g (1000 mg) every 6 hours or 650 mg every 4 hours, with dosing intervals of at least 4 hours between doses, and a single dose should not exceed 1 g [3]. The major concern with acetaminophen use is hepatic toxicity [3], particularly in cases of overdose (ingestion of more than 10 to 15 g in adults and 150 mg/kg in children), necessitating cautious administration in patients with existing liver disease [4]. With the rise of multimodal analgesic regimens designed to reduce opioid use in response to the opioid epidemic, non-opioid analgesics like acetaminophen have become more prominent in the perioperative period. It is widely acknowledged that incorporating acetaminophen into opioid-sparing multimodal analgesic strategies can also lessen opioid-related side effects, such as postoperative nausea and vomiting (PONV), urinary retention, and ileus [5]. Although there is debate, some trials have reported that the intravenous administration of acetaminophen reduces pain more effectively than oral [6]. Intravenous acetaminophen offers a faster onset of analgesia and may impact opioid requirements differently compared to oral acetaminophen, which is affected by opioid-induced gastrointestinal inhibition [7].

In recent years, preemptive pain control has emerged as an area of focus. Preemptive analgesia focuses on administering analgesics before the surgical procedure begins to prevent the establishment of central sensitization. This approach aims to block pain signals and reduce the overall pain experience by addressing pain before the nociceptive stimuli are introduced [8]. Otherwise, preventive analgesia is a broader approach that involves administering medications not only before but also during, and after surgery by reducing peripheral and central sensitization throughout the perioperative period [6,9]. By attenuating the impact of noxious stimuli at multiple stages, preventive analgesia aims to reduce postoperative pain intensity and analgesic requirements. In the perioperative setting, intravenous acetaminophen is suggested to have a more predictable pharmacokinetic and pharmacodynamic behavior compared to an equivalent oral dosage. Typically, clinicians administer the oral dose in the preoperative holding area, while the IV dose is administered just before anesthesia induction or during surgery [5]. This review aims to explore the timing of IV acetaminophen administration and its impact on postoperative analgesic efficacy, opioid-sparing effects, and PONV in patients undergoing major orthopedic, abdominal, or gynecological surgery.

Methods

A comprehensive literature review was conducted on PubMed, Ovid Medline, Web of Science, and Google Scholar to identify articles relevant to the timing of intravenous acetaminophen administration and postoperative outcomes in patients undergoing major orthopedic, abdominal, or gynecological surgical procedures. The search strategy included keywords such as “Acetaminophen”, “Intravenous”, “Injections”, and terms related to surgical procedures like “Knee Arthroplasty”, “Hip Arthroplasty”, “Obstetrics”, “Gynecology”, “Abdomen”, “Laparoscopy”, and “Spine” surgery. Inclusion criteria were studies that considered postoperative outcomes with IV acetaminophen administration in the perioperative setting. Exclusion criteria were any studies that were not written in the English language and studies that failed to include IV administration of acetaminophen in their protocol. There were no limitations on the year of publication. This review explores the timing of IV acetaminophen administration and its impact on postoperative analgesic efficacy, opioidsparing effects, side effects, and PONV, comparing various dosing regimens to placebo, NSAIDs, and oral acetaminophen in patients undergoing major surgeries (orthopedic, abdominal, or gynecological).

Results

Preoperative Administration

The preemptive approach, involving the use of IV acetaminophen before a surgical incision or prior to noxious stimulus, has been explored in various surgical contexts. Moon YE et al. [10] observed that preemptive administration (30 min before surgery) of a single 2g dose of IV acetaminophen resulted in a 30% reduction in hydromorphone consumption over 24 h in patients undergoing abdominal hysterectomy. Jokela et al. [11] found periodic doses (1g every 6 h) of IV acetaminophen starting at anesthesia induction reduced the total dosage of oxycodone required in laparoscopic hysterectomy patients. Similarly, Hong et al. [12] found that preemptive IV acetaminophen (1 h before induction of anesthesia and then at 6-h intervals following 24 h) demonstrated a significant reduction in postoperative pain scores, rescue analgesia, and adverse effects such as nausea and vomiting compared to placebo in patients undergoing endoscopic thyroidectomy. Hassan et al. [13] further reported improved hemodynamic stability, reduced opioid consumption, and fewer postoperative side effects when preemptive IV acetaminophen was used in cesarean deliveries compared to a preventive approach. Wang et al. [14] also found that preemptive administration of IV acetaminophen (1g within 15 min after anesthesia induction and before incision) reduced hospital LOS by 32% without significantly affecting pain scores or opioid use. Meta-analyses, such as those by Xuan et al. [15], reinforce these findings by showing modest pain relief and delayed rescue analgesia compared to placebo. Khalili et al. [9] demonstrated that both preemptive and preventive administration of IV acetaminophen effectively reduced pain and opioid consumption in lower extremity orthopedic surgeries, with the preemptive approach requiring less rescue analgesia.

Additional studies highlight the varying effects of preemptive IV acetaminophen. Evidence suggests that its administration can reduce postoperative opioid consumption, improve analgesia, and lower associated side effects like constipation of hospitalization costs, particularly in procedures such as abdominal hysterectomy and orthopedic surgeries [16-18]. Beyond its analgesic benefits, preemptive IV acetaminophen has been associated with improved hemodynamic stability during cesarean sections and a reduction in severe postoperative shivering, likely due to its influence on thermoregulation [13,19-20] However, other studies present contrasting results. Towers et al. [21] and Rindos et al. [22] found no significant reductions in pain scores or opioid consumption with preincisional administration of IV acetaminophen in cesarean delivery and laparoscopic hysterectomy, respectively. Similarly, Politi et al. [23] and Cain et al. [24] observed no notable advantages of IV acetaminophen over oral formulations in reducing opioid consumption or improving pain scores in hip and knee arthroplasty and open gynecologic surgeries, respectively. While Turner et al. [25] also found no significant differences in pain scores, opioid use, or satisfaction when administering IV acetaminophen preemptively (10-30 min prior to incision) in patients undergoing pelvic organ prolapse repair, Sacha et al. [18] found no benefit on pain scores or time to discharge, but it did reduce opioid use and constipation in patients undergoing oocyte retrieval, highlighting the variability in outcomes on specific surgical and clinical context. Apfel et al. [26] in a systematic review of randomized controlled trials that included 30 studies with 2364 patients undergoing general surgery found that IV acetaminophen compared to placebo reduced nausea (mainly mediated through superior pain control) when given prophylactically either before surgery or before arrival in the postanesthesia care unit, but not when given after the onset of pain.

Perioperative Administration (Preventative Combination)

Preventive administration of IV acetaminophen, delivered after the noxious stimulus, has been shown to reduce opioid use and enhance recovery. Altenau et al. [27] demonstrated that preventive administration of IV acetaminophen (within 60 min of skin incision) significantly reduced postoperative oral narcotic consumption, without impacting pain scores in cesarean patients. In a similar context, Kiliçaslan et al. [28] reported a reduction in tramadol use and pain scores following intraoperative administration of IV acetaminophen (15 min before the end of surgery) in cesarean deliveries, compared to placebo. Cattabriga et al. [29] also observed reduced morphine consumption and improved pain control in cardiac surgery when IV acetaminophen was administered intraoperatively (at skin closure) as part of a multimodal approach. Other benefits of preventive administration include faster recovery timelines. Rizkalla et al. [30] found that preventive administration (at skin closure) was associated with faster PCA discontinuation and advancement to solid food in posterior spinal fusion (PSF) patients, while also reducing postoperative opioid consumption. In pediatric and adolescent PSF patients, Kim et al. [31] similarly found that IV acetaminophen reduced opioid use without significant drug-induced adverse effects. Mamoun et al. [32] found intraoperative administration of IV acetaminophen (15 min before the end of surgery) reduced pain intensity after cardiac surgery, although opioid consumption remained unchanged. Subramaniam et al. [33] reported that preventive administration of IV acetaminophen reduced antiemetic requirements in major abdominal surgery, though pain relief and opioid use were similar to placebo. On the other hand, Deng et al. [34] reported that a single intraoperative dose (1g) of IV acetaminophen administered at skin closure during spine surgery did not produce an opioid-sparing effect or reduce opioid-related adverse effects. Hickman et al. [35] found no equivalent outcomes between preoperative oral and intraoperative IV acetaminophen in hip and knee arthroplasty, emphasizing the limited advantage of IV administration in these contexts. Sacha et al.18 investigated the efficacy of preoperative IV acetaminophen (1g) compared to oral (1g) and placebo in women undergoing oocyte retrieval and no significant differences were found in postoperative pain scores, time to discharge, or embryology outcomes between the groups. While not statistically significant, women who received IV acetaminophen had lower opioid requirements and reported less constipation. These findings suggest that routine preoperative IV acetaminophen may not be warranted for pain management after oocyte retrieval. Using a retrospective cohort study Miler et at. [36] investigated the impact of a multidisciplinary initiative to prioritize oral IV acetaminophen in adult patients undergoing non-cardiac surgery. Data was analyzed from before and after the initiative and showed increased oral acetaminophen use and decreased IV use, no significant differences in perioperative narcotic consumption, pain scores, time to PACU discharge, or the incidence of PONV.

Postoperative administration of IV acetaminophen, initiated in the recovery room or shortly after surgery, plays a critical role in multimodal pain management. Huang et al. [37] demonstrated significant reductions in opioid consumption and improved pain scores within 24 h following total knee arthroplasty. Similarly, Aksoy et al. [38] found that IV acetaminophen was as effective as subcutaneous bupivacaine in reducing pain and opioid consumption compared to placebo, although bupivacaine provided superior immediate pain relief. Comparisons between IV and oral acetaminophen highlight the cost-effectiveness of oral formulations. Wilson et al. [39] reported no significant differences in pain scores or opioid use between IV and oral acetaminophen in cesarean patients. Takeda et al. [40] observed significant reductions in fentanyl use and pain scores after total hip arthroplasty.

Dosing Considerations for IV Acetaminophen

The dosing strategy for acetaminophen in the perioperative setting can be influenced by its route of administration. IV acetaminophen achieves peak plasma concentrations within 15 min, providing rapid analgesic effect within 5 min and lasting up to 4 h. This is notably faster compared to oral and rectal forms, which reach peak levels in 45-60 min and 4 h, respectively [41]. The recommended dose for IV acetaminophen in adults is 1g, with a maximum daily dose of 4g/day. However, it has been suggested that better analgesia could be obtained with a 2-g starting dose. Piguet et al. [42] demonstrated a significant, dose-dependent correlation between acetaminophen’s plasma levels and its analgesic effects in healthy volunteers, suggesting a dose-dependent central antinociceptive effect.

Some authors have reported a significant reduction in opioid consumption with IV acetaminophen, others have found no such effect. This inconsistency has been accredited to variations in dosing and administration duration, which ranged from 24 to 48 h in their study, potentially due to financial considerations [43]. Remy et al.2 reported the standard dose of 1g of IV acetaminophen every six h generally results in less than 10 mg reduction in opioid use over 24 h. In contrast, Juhl et al. [44] found that a 2 g starting dose of IV acetaminophen was more effective than 1 g every six h for postoperative pain following third molar surgery, with no significant difference in safety. However, these findings should be interpreted cautiously, as additional research is needed to determine the applicability of this dosing regimen to major surgical procedures [44]. Gregoire et al. [45] evaluated the efficacy of IV paracetamol with a 2 g starting dose to a total of 5 g dose administered in the first 24 h. It was found that plasma concentrations following repeated 1-g doses were approximately 35% lower than those measured after 2-g dose, with no evidence of drug accumulation [45]. Acetaminophen’s pharmacokinetics remained stable, with concentrations far below the toxic threshold, demonstrating both clinical and biological safety in healthy subjects. To assess the risk of liver damage, researchers measured peak and 4-h post-dose paracetamol levels. The highest level recorded after a 2-g infusion in healthy subjects was 115 mg/ml, with no adverse effects reported. The average levels at 4 h were: 11.4 mg/ml (after the first 2-g infusion), 7.3 mg/ml (after the second 1-g infusion), and 6.4 mg/ml (after the fifth 1-g infusion). All these levels were well below the 150 mg/ml threshold for potential liver toxicity [45]. This suggests that a more consistent or higher dose of IV acetaminophen may be needed to achieve significant opioid-sparing effects. Further research is required to explore the potential of new IV acetaminophen dosing regimens for enhancing analgesia and reducing opioid use [2]. Table 1 include the effect of timing of perioperative administration of IV acetaminophen.

Table 1: Studies on effect of timing (pre-post incisional) of intravenous acetaminophen administration on analgesic efficacy (opioid-sparing), side effects and recovery

Discussion

The timing of intravenous (IV) acetaminophen administration during the perioperative period has been studied extensively to evaluate its effects on postoperative pain scores, postoperative nausea and vomiting (PONV), and rescue opioid analgesic use.

The timing of IV acetaminophen administration during the perioperative period has shown the following: (1) Preemptive administration, given before surgical incision or anesthesia induction, demonstrated to reduce opioid consumption, better postoperative pain control, reduce side adverse effects like postoperative nausea and vomiting (PONV) and improve hemodynamic stability and reduce severe postoperative shivering in cesarian section [10-13] Despite the positive findings, some studies have shown that the benefits of preemptive administration may not be as pronounced for all surgical procedures [23-24]. Intraoperative and preventive administration has been shown to reduce opioid consumption, improve recovery outcomes, and faster mobilization [30-31]. However, in some studies, intraoperative administration did not reduce opioid use or pain. Postoperative administration, often shows comparable outcomes to oral acetaminophen, suggesting that oral routes may offer comparable benefits at lower costs for certain patient populations [39]. Despite this, IV acetaminophen has been associated with faster onset of analgesia [40]. Dosing considerations indicate that standard doses of IV acetaminophen (1 g every six h) are effective, but higher doses (2 g) may enhance analgesia and opioid-sparing effects [44-45]. Some studies [2,44-45]. show stable pharmacokinetics and safety, but further research on higher doses and financial factors is needed.

In conclusion, the administration of IV acetaminophen during the perioperative period has been studied for its impact on postoperative pain management, opioid-sparing effects, and side effects such as PONV. Evidence supports its effectiveness compared to placebo, oral acetaminophen, and NSAIDs in reducing pain scores and opioid consumption, particularly in orthopedic surgeries like total knee and hip arthroplasty. The timing of administration whether preincisional, or postincisional significantly influences its efficacy. Preincisional administration is particularly effective in reducing opioid requirements and mitigating adverse effects in cesarean surgeries, while intraoperative use enhances recovery metrics. Postoperative administration remains crucial in multimodal analgesia, especially when oral alternatives are not viable. Clinicians should consider incorporating IV acetaminophen into multimodal analgesia regimens, with further research needed to establish standardized guidelines and explore its role in various surgical contexts and timings. Overall, IV acetaminophen is a valuable component of multimodal analgesia, contributing to improved patient outcomes and potentially reducing opioid

dependence in the postoperative period. Future prospective research on studies on timing of IV administration still need to be specifically conducted in order to reach a clear conclusion on its optimal use.

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