Perioperative N-acetylcysteine: evidence and indications

Abstract

Nonopioid analgesics serve to improve analgesia and limit side effects and risks of perioperative opioids. N-acetylcysteine (NAC), the primary treatment of acetaminophen toxicity, may have perioperative indications, including analgesia. NAC impacts glutathione synthesis, oxidant scavenging, glutamate receptor modulation and neuroinflammation. Potential perioperative benefits include arrhythmia prevention after cardiac surgery, decreased contrast-induced nephropathy, improved post-transplant liver function and superior pulmonary outcomes with general anesthesia. NAC may improve perioperative analgesia, with some studies displaying a reduction in postoperative opioid use. NAC is generally well tolerated with an established safety profile. NAC administration may predispose to gastrointestinal effects, while parenteral administration may carry a risk of anaphylactoid reactions, including bronchospasm. Larger randomized trials may clarify the impact of NAC on perioperative analgesic outcomes.

Plain Language Summary

Nonopioid mediations are important to help pain control after surgery and may decrease risks of opioids. N-acetylcysteine (NAC), the treatment of acetaminophen overdose, decreased inflammation and has other positive effects on the body that may help pain after surgery. Thus, NAC has been studied to prevent abnormal heart rhythms with heart surgery, help kidneys after surgery, improve the liver after liver transplant or other live surgeries and improve breathing after anesthesia. NAC may also decrease pain and the amount of pain medications needed after surgery. While NAC is generally well tolerated and considered safe, stomach upset can occur as can itching or asthma like reactions in certain patients. This review describes how NAC may improve pain, summarizes the other ways NAC may help a patient undergoing surgery, and describes potential side effects when NAC is given.

Plain language summary

Article highlights.

• N-acetylcysteine (NAC) has an established safety profile, having been used for many years for various potential clinical applications – most notably for treatment of acetaminophen-induced hepatic injury.

• NAC has multiple molecular mechanisms, serving to augment glutathione synthesis, help scavenge reactive oxygen species, and modulate neurotransmission pathways. All of these result in an anti-inflammatory and likely antinociceptive effect.

• Reasonable evidence supports perioperative NAC use for atrial fibrillation prevention in cardiothoracic surgery and for prevention of pulmonary complications related to general anesthesia.

• While some evidence supports NAC use to prevent contrast-induced nephropathy, NAC otherwise has not been consistently shown to improve perioperative renal outcomes, the most-studied perioperative indication.

• Multiple animal-model studies have demonstrated an analgesic effect of NAC administration. Perioperative analgesic studies in humans are currently few, with some studies failing to show benefit, and others demonstrating an opioid-sparing effect.

• Beneficial clinical effects of NAC are more supported with an intravenous administration route and at higher doses (approaching 150 mg/kg). Timing of administration perioperatively may play a role as well.

• NAC side effects include gastrointestinal irritability and the potential for anaphylactoid reaction and bronchospasm, especially with intravenous administration. This risk may be mitigated by slower administration rates and avoiding use in patients with significant reactive airway disease.

1. Introduction

Surgery generates nociceptive signals, and opioids inhibit nociception and decrease arousal [1]. Thus, the perioperative period is frequently a time of opioid exposure. Unfortunately, perioperative opioid exposure may be associated with a range of adverse effects, including new persistent postoperative opioid use [2]. Higher intraoperative opioid doses have also resulted in higher postoperative pain scores [3]. Accordingly, many patients continue to have poorly managed postoperative pain [4].

Nonopioid analgesics can also blunt perioperative nociception. Although multimodal analgesia was classically focused on the postoperative period, it is increasingly incorporated intraoperatively to reduce opioid requirements [5–7]. However, some analgesic adjuncts may have only a modest impact on pain, a small therapeutic index for safety, and may not be appropriate for all patients or procedures [7]. Thus, there is a need to investigate potential additional nonopioid medications to improve perioperative analgesia and limit the need for opioid therapy.

N-acetylcysteine (NAC) is a cysteine prodrug and glutamate modulator that promotes homeostatic regulation of glutamate by astrocytes [8]. Well known as the treatment for acetaminophen-induced hepatotoxicity [9], NAC also has antioxidant, anti-inflammatory and antinociceptive effects through different molecular pathways [10]. Given these broad biochemical effects, NAC has been studied for multiple perioperative uses, with analgesic outcomes becoming a more recent focus.

This article will serve to compile and unify evidence from the large, varied body of literature regarding perioperative NAC use. As non-analgesic outcomes comprise the bulk of NAC literature focus to date, the major studied perioperative indications will be assessed for strength of evidential support. Additionally, emerging evidence investigating a novel, more broadly applicable use for analgesia will be highlighted, along with an evidence-based discussion of potential mechanisms for proposed analgesic effect. A review of practical applications and side effects will finally be included in order to serve as an all-encompassing reference for perioperative NAC use, which may be used to guide further studies of the analgesic potential of this drug.

2. NAC & analgesic effect: a mechanistic overview

As a precursor to the critical antioxidant glutathione [11] and with profound antioxidant properties, NAC may have therapeutic potential in various medical conditions associated with oxidative stress and inflammation. NAC enhancement of glutathione synthesis and direct scavenging of reactive oxygen species has been highlighted in studies utilizing NAC to mitigate the symptoms of ethylmalonic encephalopathy [12] and Alzheimer’s disease [13]. Similarly, NAC’s antioxidant action and ability to modulate kinin B1 receptor expression may alleviate sensory polyneuropathy, hypertension and metabolic parameters associated with diabetes and insulin resistance, as diabetes mellitus is associated with depletion of cellular antioxidants and an increase in reactive oxygen species levels with resultant protein damage [14].

NAC’s multifaceted mechanisms of action (Figure 1) suggest a promising therapeutic role as an analgesic through glutathione synthesis enhancement, direct reactive oxygen species scavenging, inhibition of NF-κB activation, modulation of neuroinflammatory pathways and mitochondrial protection. As described above, NAC promotes production of glutathione [15] and supports cellular antioxidant defenses [16]. These actions are essential in reducing oxidative stress and inflammation, which are underlying contributors in many chronically painful conditions including inflammatory pain, neuropathic pain and cancer related pain [17]. Further, NAC directly neutralizes reactive oxygen species, mitigating oxidative stress at a cellular level [18]. This direct scavenging action contributes to the preservation of cellular integrity and function, which is crucial in preventing and mitigating pain associated with oxidative stress and inflammation [19]. By modulating cellular signaling pathways and inhibiting the activation of NF-κB, NAC reduces the production of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, thereby exerting anti-inflammatory and potentially analgesic effects [20]. Additionally, NAC can modulate neuroinflammatory pathways [21] and influence homeostatic regulation of neurotransmitter systems, particularly glutamate [8]. As all metabotropic glutamate receptor subtypes, except for subtype 6, are highly enriched within nociceptive pathways and have been demonstrated to play a critical role in both pain transmission and the processing of both acute and chronic pain, NAC-mediated regulation of this signaling may enable its analgesic action [22]. Similarly, recent studies have identified an additional novel mechanism for NAC in disrupting nerve growth factor activity at the TrkA receptor, a known nociceptive pathway [23]. These findings suggest that NAC can engage a neuroprotective mechanism that can indirectly contribute to its analgesic effects and may be particularly relevant in neurodegenerative diseases like Alzheimer’s disease. Finally, NAC's protective effect on mitochondria [24] ensures the maintenance of cellular energy metabolism and prevents apoptosis, which is significant in conditions where mitochondrial dysfunction contributes to pain and disease progression. Moreover, emerging evidence indicates that mitochondria may play a direct role in pain sensory processing. Accordingly, NAC-mediated modulation of mitochondrial function could be leveraged to attenuate or eliminate pain [25]. By chelating harmful metals and reducing their bioavailability and toxicity, NAC decreases the production of free radicals, further contributing to its antioxidant and analgesic properties, and potentially improving postoperative outcomes for patients requiring prosthetics with metals linked to systemic toxicity such cobalt and chromium [26].

Figure 1.

Mechanisms of action of N-acetylcysteine. Solid arrows represent direct mechanisms of action of N-acetylcysteine, dotted lines indicate ultimate downstream physiologic effects.

ROS: Reactive oxygen species.

3. Perioperative NAC: a review of literature

NAC has also been used to prevent and treat many systemic concerns throughout the perioperative period. Organ-level ischemic injury and ischemia-reperfusion injury are associated with various postoperative complications, including postoperative renal failure, hepatic failure and cardiac arrhythmia [27,28]. Liberal use of oxygen while under anesthesia may directly contribute to hyperoxia-mediated oxidative stress [29], and anesthetic agents themselves have been postulated to induce oxidative stress damage [30]. NAC has intrinsic antioxidant properties which may dampen mitochondrial dysfunction, decrease cell damage and reduce the overall inflammatory response to anesthesia and surgery [27,31]. Thus, most perioperative NAC studies have investigated outcomes related to inflammation and oxidative stress by assessing postoperative complications ranging from global surgical outcomes, including mortality, to organ-specific outcomes involving the kidneys, heart, liver and lungs (Table 1). Notably, only a few studies have directly assessed analgesia as a primary outcome. Additionally, while the interplay between perioperative inflammation, postoperative pain and nonanalgesic outcomes like delirium has been more extensively studied with perioperative nonsteroidal anti-inflammatory drugs [32], NAC is postulated to have similar anti-inflammatory benefits.

Table 1.

Summary of meta-analyses on the impact of perioperative N-acetylcysteine for protection, prevention, or treatment of postoperative organ dysfunction.

Publication	Improved perioperative mortality	Renal protection or improved function	Atrial fibrillation prevention	Improved liver function after transplant	Ref.
Jia et al., 2023	N/A	N/A	N/A	+	[33]
Tan et al., 2022	-	-	N/A	N/A	[34]
Zhao et al., 2022	-	+	+	N/A	[35]
Fernandes et al., 2021	N/A	-	N/A	N/A	[36]
He et al., 2019	-	+	N/A	N/A	[37]
Pereira et al., 2019	-	-	-	N/A	[38]
Chen et al., 2018	N/A	-	N/A	N/A	[39]
Ali-Hasan-al-Saegh et al., 2016	+	+	+	N/A	[32]
Rababah et al., 2016	-	-	N/A	N/A	[40]
Liu et al., 2014	+	N/A	+	N/A	[41]
Ali-Hassan-Sayegh et al., 2014	N/A	N/A	+	N/A	[42]
Gu et al., 2012	N/A	N/A	+	N/A	[43]
Wang et al., 2011	-	-	-	N/A	[44]
Ho & Morgan, 2009	-	-	N/A	N/A	[45]
Adabag et al., 2009	-	-	N/A	N/A	[46]
Nigwekar & Kandula, 2009	-	-	N/A	N/A	[47]
Baker et al., 2009	-	-	+	N/A	[48]
Naughton et al., 2008	-	-	-	N/A	[49]

+: Statistically significant supportive evidence found for the stated outcome.

-: No significant supportive evidence was found for stated outcome.

N/A: The stated outcome was not discussed within the publication.

3.1. Materials & methods

A comprehensive literature review was performed investigating the most common perioperative indications of NAC use. The following sections are grouped by outcome of interest, with discussion focused on meta-analyses when available, supplemented by individual studies as appropriate or when meta-analysis-level evidence does not exist. Overall grade of evidence within the existing literature is classified for major outcomes in Table 2. Moderate-level evidence suggests that most meta-analyses or studies investigating a particular outcome found significantly supportive results for NAC use. Modest or emerging evidence suggests that some individual studies have found statistically significant support for NAC use for a particular outcome, though overall results may be limited in quantity or display only a mild improvement in the outcome. Minimal to no evidence suggests that a majority of meta-analyses or studies investigating the outcome either failed to find significant supportive results, or otherwise displayed low-quality evidence at high risk of bias, and therefore NAC cannot be recommended for these outcomes based on current evidence.

Table 2.

Summary of common indications for perioperative N-acetylcysteine use and strength of evidence.

Moderate evidence	Modest/emerging evidence	Minimal to no evidence	Ref.
Atrial fibrillation prevention	Perioperative analgesia	Improved renal function following major surgery	[32,35,36,41–43,45,48,50,51]
Improved pulmonary outcomes after general anesthesia	Prevention or minimization of contrast-induced nephropathy	Decreased liver dysfunction following hepatectomy	[52–65]
	Decreased liver dysfunction and improved graft survival rate following liver transplant	Decreased perioperative mortality	[33–35,37,38,40,44–49]

3.2. Surgical mortality

A large systematic review examined the use of antioxidant treatments, including NAC, on mortality and other global adverse events [29]. When NAC was considered as part of a larger analysis of antioxidant agents, including vitamins C, E and melatonin, the authors found a 26% relative risk reduction of mortality in over 8000 surgical patients treated with antioxidants; however, findings were considered “low quality” of evidence due to a high risk of bias and imprecision. In subgroups of patients in which NAC was the only antioxidant given, mortality was significantly reduced in at the “longest follow-up” time. However, mortality reductions were not significant at the 30-day mortality estimate in the NAC subgroups. Further, a subgroup analysis of studies deemed “low risk of bias” did not demonstrate a significant mortality benefit on their own. While 18 other meta-analyses [33–49,66] investigated the use of perioperative NAC, many of these analyzed mortality as a secondary outcome or did not address it specifically. Of these, two meta-analyses found a statistically significant mortality benefit [36,41], five did not discuss mortality [33,34,39,42,43], and eleven failed to find a significant mortality reduction [35,37,38,40,44–49,66]. Notably, the two supportive meta-analyses [36,41] analyzed the same ten studies to conclude a mortality benefit for NAC, while the larger, negative meta-analyses include additional sources. In summary, while a preponderance of evidence fails to support a mortality reduction with perioperative NAC, individual analyses have come to this conclusion with low-quality evidence, and none have suggested increased mortality with NAC.

3.3. Renal function: cardiac & noncardiac surgery

The impact of NAC on renal function after cardiac surgery has been extensively studied and is by far the most common perioperative use described. Cardiac procedures requiring cardiopulmonary bypass (CPB) have an acute renal failure incidence of up to 30%, with up to –6% of patients requiring renal replacement therapy, significantly increasing perioperative mortality [67]. The mechanism of renal injury with CPB is multifactorial. While hypoperfusion likely plays a role, oxidative stress and subsequent renal tissue damage from reactive oxygen species occurs due to both ischemia-reperfusion injury and activation of inflammatory cascades when blood is exposed to the CPB circuit [37]. NAC has been proposed to potentially mitigate this process as an antioxidant.

In eighteen relevant perioperative NAC meta-analyses, nine investigated the effect of NAC on renal function in cardiac surgery as the primary objective [33,35,37,38,41,44,47,48,66], three discussed general NAC use in cardiac surgery with frequent mention of renal outcomes [40,45,49], and two focused on renal outcomes in noncardiac surgery [43,46]. While over half of the meta-analyses focused specifically on this issue and three others evaluated the incidence of postoperative acute kidney injury (AKI), there are conflicting results. Three meta-analyses concluded that intravenous (IV) NAC significantly decreased the incidence of postoperative AKI after cardiac surgery compared with control [odd ratios (OR) for AKI 0.7 [41], 0.77 [35], and 0.84 [44]]. While these modest reductions in AKI are statistically significant, six separate meta-analyses dedicated to answering this question failed to report significant findings [33,37,38,47,48,66], and three other meta-analyses of general NAC use in cardiac surgery did not note a significant reduction in AKI when NAC was administered [40,45,49].

An important distinction is pointed out by Tan et al. who noted in their meta-analysis that while their overall results failed to show a significant effect, NAC dosage seemed to be correlated with individual study results. Specifically, only one perioperative high-dose NAC study (150 mg/kg preoperative followed by 50 mg/kg for 6 h) [52] found a significant reduction in perioperative AKI, and all other high-dose papers with a later dosing period trended toward AKI reduction, even though not all reached statistical significance. Thus, higher dosage and to a lesser extent earlier administration may be key in seeing a significant AKI reduction in this use. Regardless, with nine meta-analyses failing to find significant results for NAC in AKI reduction after cardiac surgery, the data is at best mixed and limited by heterogeneity.

Multiple studies have also focused on renal outcomes following noncardiac procedures. Two meta-analyses are particularly notable [43,46]. Ho et al. investigated the potential for NAC to prevent acute renal failure in all major surgery, including major vascular, thoracic, gastric and hepatobiliary surgeries in addition to cardiac procedures. This analysis failed to find significant improvement in rates of postoperative acute renal failure with perioperative NAC administration. Notably, the authors only included studies in which radiocontrast was not used during surgery, since preemptive NAC can exert a protective effect against contrast-induced renal injury [53,68]. As they may have excluded the patients that could have had the most benefit, the authors concluded that while their data does not support NAC use in non-contrast procedures, they would recommend NAC prophylaxis as a reasonable intervention in to prevent radiocontrast nephropathy. They further stated that they did not find NAC to increase any detrimental effects, including surgical bleeding or blood product use. A separate meta-analysis of preventative strategies for AKI in patients undergoing abdominal aortic aneurysm repair by Fernandes et al. included various interventions and was not specific to NAC [43]. Studies examined administration of either oral NAC alone (which may be potentially inferior to IV administration [44]), or as part of a multi-antioxidant regimen with other supplements including vitamins and mannitol, potentially confounding NAC-specific results. They did not find NAC to improve renal outcomes. In conclusion, NAC use to improve renal outcomes in general surgery may be limited to instances of contrast-induced nephropathy, with minimal evidence for renal benefit in non-contrast surgeries.

3.4. Atrial fibrillation prevention

Postoperative atrial fibrillation (AF) prevention has also been extensively evaluated as a NAC target. AF is the most common arrhythmia after cardiac surgery, with incidence rates of 2–50%, and increased levels of plasma proinflammatory markers have been associated with AF incidence [28]. Given the antioxidant and anti-inflammatory mechanisms of NAC, it has been evaluated as a potential therapy in this area. Of 18 perioperative NAC meta-analyses within the literature, seven named either AF prevention, arrhythmia prevention or general complications including AF as their primary focus [34,36,39–41,45,49], while two AKI-based meta-analyses also investigated AF or arrhythmia prevention [38,44]. Within the relevant studies, six analyses [34,36,39–41,44] found that NAC significantly reduced postoperative AF versus controls [OR: (0.5[33]–0.74[42])], while three meta-analyses did not note a significant improvement in NAC subjects [38,45,49]. Variations between studies may explain these varied results, including: limiting evaluation to new-onset postoperative AF specifically versus including patients with preexisting AF; varied NAC dosing strategies and routes of administration between studies; inclusion of all postoperative arrhythmias in analysis, rather than limiting scope to AF only. Overall, six of nine meta-analyses demonstrated significant reductions in AF incidence, and no studies described deleterious effects. However, conclusions are limited by heterogeneity between studies, and data would be strengthened by larger, randomized, placebo-controlled multicenter trials.

3.5. Liver transplant & hepatectomy

The most well-known and well-studied clinical use of NAC is in treatment of acute liver failure after acetaminophen overdose. Through repletion of glutathione stores and general antioxidant and anti-inflammatory activity, NAC has been proven beneficial for liver failure in this setting and has also been studied in nonacetaminophen induced acute liver failure [54] with inconsistent results. Similarly, NAC has been investigated as a perioperative agent in hepatectomy and liver transplant surgery, where ischemia-reperfusion injury can play a large role in postoperative liver function. One large meta-analysis of thirteen studies with over 1100 liver transplant cases evaluated NAC use within liver transplant surgery in which NAC was given to donor, recipient or both [42]. Overall analysis found that NAC significantly improved incidence of primary graft nonfunction, postoperative liver function (as measured by peak liver enzyme levels), postoperative complication rate, and 2-year graft survival rate. Subgroup analysis suggests that NAC administration to transplant recipients specifically is most associated with improved outcomes. Overall patient survival was not affected by NAC administration, and authors noted that NAC use was associated with a mildly increased transfusion requirement. As with prior end points, the authors noted that heterogeneity between studies limited the quality of results.

Randomized controlled trials have also evaluated the role of NAC in hepatectomy, including living donor hepatectomy [55] and therapeutic liver resection. Despite generally supportive evidence for use in liver transplant, the handful of studies investigating hepatectomy procedures are less favorable. Ammar et al. did find that NAC administration significantly improved serum lactate levels and eventually international normalized ratio (INR) levels postoperatively but did not affect renal function, intensive care unit (ICU) stay, or general complication rate [55]. Three other randomized studies each failed to show significant improvements in overall rates of liver failure, ICU length of stay or mortality [56,57,69]; although, one did report an improvement in liver function tests when ischemic time was 70 min or greater [69]. In summary, in contrast to favorable evidence supporting NAC use in liver transplant, clinically important improvement in outcomes have not been demonstrated in hepatectomy.

3.6. Pulmonary outcomes: thoracic & nonthoracic surgery

After treatment for acetaminophen toxicity, NAC is next best known as a mucolytic agent. Whether given via inhalational or peroral route, NAC has been shown to dilute mucus secretions and facilitate ventilation [58]. This has prompted multiple studies investigating the perioperative use of NAC to prevent postoperative pulmonary complications in various surgical settings, though no meta-analyses exist within the literature specific to pulmonary outcomes. In a prospective study of 42 liver transplant patients randomized to receive inhaled NAC vs placebo, NAC group patients experienced significantly shorter ICU stays and length of hospitalization overall, in addition to a significantly lower 12-month mortality specifically related to pulmonary causes [59]. Likewise, a large retrospective analysis examined over 2000 general surgery patients receiving inhaled NAC therapy and found NAC was associated with a significantly lower incidence of postoperative pulmonary complications, postoperative ICU admission, postoperative mechanical ventilation, and need for sputum suctioning compared with a group receiving ambroxol therapy [60]. Multiple other studies with IV NAC noted improvements in rates of postoperative acute lung injury [61], pulmonary function test values in chronic obstructive pulmonary disease patients [62], systemic oxygenation as measured by postoperative alveolar–arterial gradient or PaO2/FiO2 ratios [63–65], and pulmonary vasodilation [70]. Overall, eight of 12 clinical studies investigating perioperative NAC use and pulmonary outcomes found significantly positive results [59–65,70]. Negative studies in which NAC failed to show significant improvement in postoperative pulmonary complications, frequently used very low-dose NAC (600 mg total) compared with the more common high-dose regimens [58,71,72] or examined a primary outcome of exhaled breath markers of systemic inflammation [73]. In summary, most clinical trials have noted NAC to have some measure of significant improvement in either pulmonary complications or function, including some evidence for decreased ICU admission, ventilation, and length of stay.

3.7. Analgesia outcomes: chronic pain & acute postoperative pain

Evidence for potential analgesia benefits of NAC therapy is currently limited to a few studies, though multiple prior animal model studies support an analgesic effect. Glutamate receptor-mediated analgesic activity of NAC was first observed in rodent models [74,75] and this same metabotropic glutamate receptor-mediated analgesic effect of NAC was later demonstrated in human volunteers exposed to laser stimuli pain [76]. NAC has also demonstrated promise in reducing chemotherapy-induced neuropathic pain in breast cancer patients treated with oral NAC over a 12-week period [77], and rodent models suggest that NAC likely also mediates neuropathic pain through inhibition of matrix metalloproteinases within the spinal cord [78]. NAC may additionally augment or amplify the impact of other nonopioid analgesics, as co-administration of NAC has been noted to improve the analgesic effect of acetaminophen in a dose-dependent fashion in a rodent nociception model [79]. Further, Zhou et al. [80] found that NAC can function to reduce heroin-seeking behavior in rodent models, potentially demonstrating another beneficial mechanism with regard to postoperative opioid consumption and concern for new persistent opioid use and abuse. Notably, one meta-analysis [81] assessed nine studies consisting of 863 patients with chronic pain conditions including but not limited to sickle cell disease, complex regional pain syndrome and neuropathy. They determined that while individual studies may have found significant effects on pain intensity with NAC therapy, an overall meta-analysis of included studies did not find statistical significance for pain reduction, quality of life or functional outcome improvements. Like other mentioned NAC meta-analyses, small sample size and high heterogeneity remained issues, and the authors concluded that larger randomized controlled trials were needed to further explore the impact of NAC on pain scores, opioid consumption, and new persistent opioid use.

Clinical studies evaluating acute perioperative analgesia are sparse. In a prospective trial by Mulkens et al. [50], 46 patients undergoing laparoscopic inguinal hernia repair were randomized to either IV NAC therapy (150 mg/kg) or placebo 1 h prior to surgery. After surgery, pain scores on the visual analogue scale were similar at all timepoints, and postoperative opioid use between groups was statistically not different. Further, over half of the NAC patients experienced flushing (53.8%) during the 15 min preoperative infusion with and without urticaria (23.1%) and dyspnea (15.4%). In contrast, in 31 subjects undergoing orthopedic knee surgery using a tourniquet and randomized to peroral NAC (1200 mg 1 day prior to surgery and 600 mg day of surgery), ischemic preconditioning or placebo, NAC significantly reduced postoperative morphine consumption by half (0.22 vs 0.47 mg/kg, p < 0.05) [51]. Similarly, in a prospective study by Wilson et al. of 40 subjects randomized to intraoperative NAC (150 mg/kg) or placebo during spine surgery, NAC patients received 1–22% less opioids in the first 48 h postoperative [82]. NAC patients also took longer to request pain medication and reported lower pain scores within the first 2 days after surgery. Notably, Wilson et al. did not observe the higher adverse event rate noted by Mulkens et al. and the authors theorized that this was likely due to their slower 60 min infusion rate.

In conclusion, multiple studies in animal and human subjects have found supporting evidence for an analgesic effect of NAC, particularly regarding neuropathic pain, and perioperative analgesic studies have shown potential for an opioid-sparing effect. However, larger randomized trials are needed.

4. NAC side effects

NAC can be administered orally or parenterally, with side effects dependent on method and dose of administration. For both orally and parenterally administered NAC, nausea, vomiting and diarrhea have been reported, though rates of nausea and vomiting are higher with oral route [83]. In a multicenter retrospective study of over 500 patients undergoing treatment with either IV or oral NAC or both for acetaminophen poisoning, NAC was associated with nausea and vomiting rates of 7.2 and 6.5%, respectively, in the IV group compared with 20 and 13.1% in the oral cohort [83]. For individuals with known risk factors for postoperative nausea and vomiting, careful attention to antiemetic administration and consideration of volatile avoidance may mitigate these effects. Patients with known gastrointestinal tract malabsorption may fail to absorb oral NAC appropriately, potentially resulting in reduced efficacy, and may be better served with parenteral administration [84]. Further, while the mucolytic properties of NAC [85] may provide benefit to patients with chronic bronchitis, bronchiectasis or disorders of mucus clearance, particularly if prolonged mechanical ventilation is anticipated, this must be balanced with the potential for bronchospasm as discussed below.

Parenteral NAC is associated with anaphylactoid reactions, perhaps the most worrisome side effect for anesthesiologists. Anaphylactoid reactions may be characterized by bronchospasm, pruritus, flushing, urticaria, nonurticarial rash, angioedema, stridor, chest tightness and hypotension [83]. In the previously described multicenter retrospective study of over 500 patients, pruritis (3.3%), flushing (2.0%) and urticaria (1.3%) were the most reported symptoms potentially suggestive of anaphylactoid reaction in the IV NAC cohort, with significantly lower rates in the oral cohort [83]. Reassuringly, anaphylactoid related hypotension occurred in <1% of patients in either cohort, consistent with previous studies [86]. In a similar retrospective analysis of over 6400 patients receiving IV NAC (150 mg/kg infusion over 15–60 min, then 50 mg/kg over 4 h, and 100 mg/kg over 16 h) for acetaminophen toxicity, an 8.2% anaphylactoid reaction rate was reported; however, the vast majority (75.4%) of these manifested with cutaneous symptoms only, while systemic reaction rates were less than 2% [87]. Similarly low rates of anaphylactoid reactions were noted in recent studies examining use of perioperative NAC [82,88,89] with one study not noting any adverse reactions [82]. Notably, duration of infusion may impact likelihood of adverse effects. Mulkens et al. [50] reported high rates of flushing (53.8%) without or with urticaria (23.1%) and dyspnea (15.4%) when NAC 150 mg IV was administered preoperatively over 15 min, while Wilson et al. [82] reported no adverse effects with a 60 min administration time. Given this, a longer administration time may offer the benefit of reduced anaphylactoid symptoms. Vigilance to predisposing conditions, particularly asthma and reactive airway disease, may also be critical to ensure appropriate patient selection for NAC administration to maximize benefits and minimize risks. Thus, the mucolytic benefits of NAC should be balanced with the potential for anaphylactoid reactions in patients with known reactive airway disease. While prolonged infusion times may reduce or mitigate some of these concerns, care should be taken in patients with chronic pulmonary disease or recovering from upper respiratory infections, which can induce airway hyperreactivity and thus predispose to bronchospasm [90].

NAC may have a mild anticoagulant effect; however, this is presumed to have little clinical relevance. Literature demonstrates that IV NAC may interfere with prothrombin time (PT) and INR measurements [91,92]. Pizon et al. reported a dose-dependent increase in PT when NAC was added directly to blood plasma samples, though NAC dosing was significantly higher in this in vitro study (concentrations of 250, 500 or 1000 mg/l) than suggested dosing for perioperative pain [92]. Similarly, Schmidt et al. found a decrease in prothrombin index and subsequent increase in PT in patients undergoing treatment of acetaminophen overdose without evidence of hepatotoxicity, potentially due to inhibition of clotting factors II, VII, IX, X by NAC [93]. Further, Minhaj et al. noted a statistically significant effect on INR measurement in vitro with therapeutic concentrations of NAC, though little clinical significance is suggested given that the largest INR increase was only 0.25 [94]. Importantly, these findings are relevant to decision-making regarding timing of NAC discontinuation during treatment of acetaminophen overdose rather than predicting clinical bleeding. To date, studies demonstrating an increased operative bleeding risk with NAC administration are lacking. In a small prospective study of patients undergoing open abdominal aneurysm repair, IV NAC impacted prothrombin levels but not total blood loss [95]. Further, in a recent study involving perioperative NAC administration in patients undergoing major thoracic surgery, no patient receiving NAC required reoperation for bleeding (vs two subjects in the placebo cohort) [96].

5. Conclusion

Multiple clinical therapeutic trials have demonstrated a reasonable safety profile for perioperative NAC. Beneficial outcomes have been demonstrated for arrhythmia prevention in cardiac surgery, contrast-induced nephropathy, post-transplant liver function and pulmonary outcomes after general anesthesia (Table 2). Evidence continues to evolve but remains limited regarding NAC’s analgesic potential in the acute perioperative period. Intravenous NAC at higher doses may have better analgesic effects but must be balanced with the risk of anaphylactoid reactions, which may be ameliorated by proper patient selection and slower speed of administration. Overall, the established safety profile, multiple possible analgesic mechanisms, and current body of literature support future research to more clearly characterize the analgesic potential for NAC in the perioperative period.

6. Future perspective

With multiple proposed mechanisms for analgesic effect, future studies should focus on larger scale, randomized controlled trials to further describe both efficacy and safety in the acute perioperative patient. Given that earlier administration may correlate with positive outcomes, future studies may also investigate the importance of preoperative administration in comparison with primarily intraoperative and postoperative approach. As NAC may share common anti-inflammatory mechanisms with other multimodal analgesics like NSAIDs, a more specific multimodal combination or head-to-head comparison strategy may better elucidate NAC’s unique analgesic potential, particularly as NAC may be more tolerable for NSAID-intolerant patients with renal insufficiency. Likewise, NAC’s neuroinflammatory benefits could be studied in the older adult population, with a focus on postoperative delirium and cognitive dysfunction alongside analgesia – particularly given the role of traditional opioid therapies in worsening these outcomes. A variety of surgical procedures must be studied to determine how broadly applicable any analgesic activity may be, as certain surgeries may be more suitable based on the associated pain profile. Finally, large studies that incorporate more traditional non-analgesic outcomes may serve a dual purpose, both highlighting NAC’s analgesic potential and solidifying additional perioperative benefits.

Financial disclosure

M Scofield: This author receives research funding from the Medical University of South Carolina, College of Medicine. (Translational Team Science Grant: Astrocyte Modulation and Suppression of Opioid Intake and Relapse Vulnerability; Role: Primary Investigator. SH Wilson: This author receives research funding from the Medical University of South Carolina, College of Medicine. (Translational Team Science Grant: Astrocyte Modulation and Suppression of Opioid Intake and Relapse Vulnerability; Role: Co-Investigator. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.