Intravenously Administered Nonsteroidal Anti-Inflammatory Drugs in Clinical Practice: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The topic is vital, especially in public health, but the observation period is questionable. It is well known that the overuse of antibiotics during the COVID-19 pandemic (2020-2021) increased the incidence of C. difficile infections compared to the pre-COVID-19 period (2017-2019). Thus, I am suggesting that the authors compare those two periods separately.  

The narrative review is focused on the intravenous use of NSAIDs in clinical practice. Clinical pharmacodynamics (PD) is well presented, but clinical pharmacokinetics (PK) of NSAIDs is not even mentioned. The latter issue is crucial for the decision to apply those drugs intravenously.

Accordingly, PK, as well as PK/PD of NSAIDs, should be evaluated in the available literature. The safety profile of intravenous NSAIDs should be considered in more detail and compared to their oral counterparts and to paracetamol itself. Guidelines for the management of postoperative pain should be referred to.

The research involves a broad, representative sample of hospitals from one area, and the pharmacoepidemiological method used is reliable and informative. 

Methods and Results: The authors should discuss why they covered pre-COVID-19 and COVID-19 periods in the same sample.

 

Discussion: Limitations of the study should be added.

The reference list is complete and updated.

 

There is no need to add further figures and tables.

Author Response

Reviewer 1

 

 

Comment #1

The topic is vital, especially in public health, but the observation period is questionable. It is well known that the overuse of antibiotics during the COVID-19 pandemic (2020-2021) increased the incidence of C. difficile infections compared to the pre-COVID-19 period (2017-2019). Thus, I am suggesting that the authors compare those two periods separately. 

 

 

Response

Thank you for raising this point about the influence of COVID-19–era antibiotic overuse on C. difficile infections. Our review focuses on intravenous NSAIDs for perioperative pain management, where antibiotic practices do not directly affect the efficacy or safety outcomes under discussion. We did not identify a notable shift in IV NSAID data specifically tied to the pandemic period; most studies spanned both pre- and post-2020 without highlighting major differences linked to COVID-19.

 

Therefore, it seemed reasonable to integrate the literature across the entire timespan, rather than segregating by pandemic years. However, to acknowledge the pandemic’s broader context, we have now included a brief statement in the manuscript recognizing how altered antibiotic use during COVID-19 might influence hospital infection profiles, even if it does not directly impact the conclusions drawn about IV NSAIDs.

 

Related revised manuscript text

Thirdly, five of the studies reviewed here in detail were published after 2020 and were conducted during or following the global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, unsubstantiated media reports suggested that the NSAIDs might exacerbate the signs and symptoms of COVID-19. The results of a number of robust clinical studies have now demonstrated that NSAID use is not associated with worse COVID-19 outcomes, and the European Medicines Agency (EMA), and the US Food and Drug Administration (FDA) did not advise against using NSAIDs

 

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Comment #2

The narrative review is focused on the intravenous use of NSAIDs in clinical practice. Clinical pharmacodynamics (PD) is well presented, but clinical pharmacokinetics (PK) of NSAIDs is not even mentioned. The latter issue is crucial for the decision to apply those drugs intravenously. Accordingly, PK, as well as PK/PD of NSAIDs, should be evaluated in the available literature.

 

Response

Thank you for highlighting the importance of PK data in the decision to use NSAIDs intravenously. We have expanded our manuscript to include detailed information on the absorption, protein binding, metabolism, and elimination of IV NSAIDs in both adults and children. This additional content compares oral, rectal, and IV routes, emphasizing how C_max, t_max, and half-life differ when NSAIDs are administered intravenously. We also reference pediatric studies (Khalil et al., Kokki et al., Lynn et al.) to illustrate the limited but growing evidence base in infants.

 

Related revised manuscript text

In terms of pharmacokinetics (PK, see below for more details), NSAIDs are rapidly absorbed and bind strongly to plasma proteins (mainly albumin). Oral, rectal and IV doses of ibuprofen tend to give similar area under the curve (AUC) values. Unsurprisingly, the peak plasma concentration (Cmax) value is higher for IV administration than oral administration. For ibuprofen, the physiologically inactive R isomer binds even more strongly that the active S isomer. Following IV and oral administration, the respective elimination half-lives are similar. Ibuprofen is mostly oxidized by cytochromes P450 2C9 and 2C8 in the liver, with subsequent renal excretion of the metabolites.

 

Overall, PK data for IV NSAIDs in infants are scarce. According to Khalil et al.’s multicenter study of 43 pediatric inpatients receiving IV ibuprofen, the area under the curve (AUC) from time zero to 4 h (AUC 0–4) ranged from 22.96 to 162.06 µg.hr/mL, and the peak plasma concentration (Cmax) was usually around 60 µg/mL ranged from 15.91 to 96.31 µg/mL. The median time to Cmax (tmax) was 10 minutes, and the mean (range) elimination half-life was 1.55 h (0.79–2.87). As expected, clearance and the distribution volume increased with age. By way of a comparison, the value of tmax for single-dose oral administration achieving the same Cmax is reportedly 1.5 to 2 h. Kokki et al. reported a mean (range) elimination half-life of 1.3 (0.8–1.7) h for a 24-continuous infusion and 1.5 (0.7–3.0) h for a single intravenous injection of ketoprofen 1 mg/kg. The steady state plasma concentration of ketoprofen was 2.0 µg/mL (range: 1.3-2.7) for a 24-continuous infusion, and Cmax ranged from 10.5 to 22.2 µg/mL for a single injection. (tmax was not reported) 80, 81. For single IV doses (0.5 or 1 mg/kg) of IV ketorolac in infants, Lynn et al. reported respective mean ± SD Cmax values of 1.1 ± 0.6 and 2.0 ± 11 for S-ketorolac and 2.5 ± 1.4 and 4.1 ± 1.8 for R-ketorolac.

 

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Comment #3

The safety profile of intravenous NSAIDs should be considered in more detail and compared to their oral counterparts and to paracetamol itself.

 

Response

Thank you for this observation.

 

Our review focuses on the perioperative role of IV NSAIDs, covering their indications, efficacy, and safety. We do touch upon parallels with oral NSAIDs and paracetamol, but our aim was not to comprehensively analyze all comparative data, which are already addressed in multiple meta-analyses. Since our key objective is to highlight perioperative use of IV NSAIDs, an exhaustive comparison with oral forms or paracetamol would extend beyond our intended scope.

 

Nonetheless, we have added references and summarized relevant literature that indicate a broadly similar safety profile among IV NSAIDs, oral NSAIDs, and paracetamol, particularly in short-term surgical settings. We hope this clarification underscores why we maintained a focused approach for this narrative review.

 

 

Related revised manuscript text

In the studies reviewed here, the overall safety profile appeared to be similar for ibuprofen, paracetamol, and ketorolac (Table 1). Peri-operative adverse events (especially bleeding) were often infrequent or absent. In Ahiskalioglu et al.’s study, the incidences of nausea and vomiting were lower even in the ibuprofen group than in the saline placebo group.

 

This off-label use by practitioners might be encouraged by clinical trial data showing that the pharmacokinetic and short-term safety profiles of IV ibuprofen in very young patients (1–6 months of age) are similar to those in older children. Lastly, diclofenac solutions for infusion (25 mg/ml) are authorized for short-term use in patients aged 16 and over in the following indications: acute rheumatic inflammation, acute back pain, nerve root pain and renal colic; hence, diclofenac for infusion is not indicated in general surgical settings.

 

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Comment #4

Guidelines for the management of postoperative pain should be referred to.

 

Response

Thank you for pointing out the need to reference postoperative pain management guidelines.

 

We have now strengthened our discussion of these guidelines in the revised manuscript, highlighting the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ recommendations. We have also included the European Society for Paediatric Anaesthesiology’s guidelines, which emphasize IV NSAIDs in multimodal strategies for various pediatric surgeries.

 

Related revised manuscript text

The core principle of multimodal postoperative analgesia including paracetamol and/or NSAIDs (in the absence of contraindications, such as patients undergoing coronary artery bypass graft surgery) has been endorsed as a strong recommendation with high-quality evidence by the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. The guideline suggested that IV and oral administrations were similar for pain relief, the onset of action might be faster with IV administration. According to the guidelines published by the European Society for Paediatric Anaesthesiology (EPSA), the consistent intra- and postoperative use of non-opioid drugs (including NSAIDs has an opioid-sparing effect and is a cornerstone of intraoperative pain management. The EPSA recommends (if available) an intravenous paracetamol/NSAID after the induction of anesthesia and throughout the postoperative period for several types of surgery, including limb fracture repair, Nissen fundoplication (open and laparoscopic), thoracoscopy/thoracotomy, appendicectomy, hypospadias repair, and the correction of congenital hip dislocation. The EPSA’s dose level suggestions are 0.5 to 1 mg per kg (up to 30 mg) for a single intraoperative dose and 0.15 to 0.2 mg per kg (up to 10 mg) every 6 h (for no more than 48 h) for ketorolac 1 mg per kg every 8 h for ketoprofen, and 10 mg per kg every 8 h for ibuprofen.

 

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Comment #5

Methods and Results: The authors should discuss why they covered pre-COVID-19 and COVID-19 periods in the same sample.

 

Response

Thank you for asking about our choice to combine the pre-COVID-19 (2017–2019) and COVID-19 (2020–2021) periods.

 

Our priority was to present a unified overview of intravenous NSAIDs in perioperative care. We did not identify a marked shift in the clinical or pharmacological findings when the pandemic began, and most studies—including large-scale trials and meta-analyses—did not separate data by these timeframes. Likewise, guidelines for perioperative NSAID use did not undergo major changes tied to COVID-19, and available research suggests that NSAIDs are not associated with worse COVID-19 outcomes. Consequently, it seemed reasonable to keep the literature from both periods combined, rather than dividing our analysis by these intervals.

 

Related revised manuscript text

Thirdly, five of the studies reviewed here in detail were published after 2020 and were conducted during or following the global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, unsubstantiated media reports suggested that the NSAIDs might exacerbate the signs and symptoms of COVID-19. The results of a number of robust clinical studies have now demonstrated that NSAID use is not associated with worse COVID-19 outcomes, and the European Medicines Agency (EMA), and the US Food and Drug Administration (FDA) did not advise against using NSAIDs

 

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Comment #6

Discussion: Limitations of the study should be added.

 

Response

Thank you for suggesting that we add a dedicated limitations section.

 

We have now appended a paragraph titled “Study strengths and limitations” at the end of the Discussion. This new section acknowledges that our review is not systematic and is primarily focused on Europe, and that some of the studies included were conducted during or after the COVID-19 pandemic.

 

Related revised manuscript text

Study strengths and limitations

The present narrative review had several strengths. Firstly, we covered a broad, topical issue with immediate clinical relevance. Secondly, we reviewed publications available solely in French, as well as those in English.

Our review also had limitations. Firstly, it was not systematic. However, several systematic reviews of some of the subtopics addressed here are available. Secondly, in view of the investigators’ affiliation, the review was centered on practice in France and Europe, and cannot be extended to all healthcare systems and clinical frameworks. Thirdly, five of the studies reviewed here in detail were published after 2020 and were conducted during or following the global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, unsubstantiated media reports suggested that the NSAIDs might exacerbate the signs and symptoms of COVID-19. The results of a number of robust clinical studies have now demonstrated that NSAID use is not associated with worse COVID-19 outcomes, and the European Medicines Agency (EMA), and the US Food and Drug Administration (FDA) did not advise against using NSAIDs. On the contrary, some studies even found a modest survival benefit for treatment with NSAIDs.

 

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Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This narrative review provides an overview of the safety and efficacy of intravenous NSAIDs when used at various doses and regimens in clinical practice. It appears to be well-written, based on a comprehensive review of the available literature. The conclusion is appropriately derived and well-aligned with the purpose of the narrative review. However, I have a few comments.

First, there seems to be an issue with sentence connection in lines 90-93: "In order to~ NSAID use." Please review this sentence.

Second, if there are any prior studies evaluating the cost-effectiveness of genetic testing for NSAID administration, it would be beneficial to mention them in section 2.7.6.

 

I hope these suggestions are helpful.

Author Response

 

Reviewer 2

 

Comment #1

First, there seems to be an issue with sentence connection in lines 90-93: "In order to~ NSAID use." Please review this sentence.

 

Response

We do agree.

We reviewed and rephrased the sentence.

 

Related revised manuscript text

The primary objective of the present narrative review is aims to provide an updated evaluation of the efficacy, safety, and clinical use of intravenous NSAIDs for perioperative pain management in adults and children. In order to highlight certain aspects of IV NSAID use.

 

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Comment #2

Second, if there are any prior studies evaluating the cost-effectiveness of genetic testing for NSAID administration, it would be beneficial to mention them in section 2.7.6.

 

Response

Thank for you insightful suggestion.

The section 2.7.6 has been renamed 6.6 to improve the flow of the article.

 

Related revised manuscript text

6.6. Pharmacogenomic profiling

Pharmacogenomic questions are increasingly being raised in the field of pain and NSAID use 113. Given their extremely wide use, NSAIDs are the primary cause of drug hypersensitivity reactions 114. These reactions may be broad (i.e. cross-reactive) or narrow (i.e. selective) and are related to the expression levels and methylation status of immune-response genes 114. For example, polymorphisms in the genes coding for COX-1 and COX-2 (PTGS1 and PTGS2, respectively) are linked to cross-reactive NSAID hypersensitivity, and the N-acetyltransferase 2 *5, *6, *7 and *14 genotypes are associated with selective NSAID hypersensitivity 115, 116. It has been known for several decades that the metabolism of NSAIDs (including ibuprofen, celecoxib, piroxicam, and diclofenac) is influenced by cytochrome P450 polymorphisms 117. The pharmacokinetics of S-ibuprofen and R-ibuprofen are affected by CYP2C9*2 and CYP2C9*3 polymorphisms and sex 118. These concerns might open up long-term perspectives for greater safety and effectiveness of IV NSAIDs.

In the era of personalized medicine, further research on inter-individual differences in reactions to and the effectiveness of IV NSAIDs is necessary.

 

 

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Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The primary aim of the review should be stated more precisely. For example, mention whether the review focuses on safety, efficacy, or guidelines for the use of IV NSAIDs in surgical settings.

Suggestion: "This narrative review aims to provide an updated evaluation of the efficacy, safety, and clinical use of intravenous NSAIDs for perioperative pain management in adults and children."

Briefly explain why IV NSAIDs are critical in multimodal analgesia, such as their role in reducing opioid dependency and managing inflammation. This provides context for the review.

The abstract would benefit from clearer structure by dividing key findings into sections (e.g., "Approved Medications," "Efficacy," and "Safety Considerations"). This improves readability.

Quantify significant findings where possible. For instance, elaborate on the "opioid sparing" effect by specifying ranges or percentages and their clinical implications.

Suggestion: "Systematic reviews and meta-analyses report that intravenous NSAIDs reduce postoperative opioid consumption by approximately 20–60%, improving pain management with fewer opioid-related side effects."

Address the limitations of current evidence, such as the lack of head-to-head randomized controlled trials, and how this impacts clinical decision-making.

Expand on the unique challenges of using IV NSAIDs in pediatric patients, such as dosage adjustments, safety concerns, and limited approved options for younger age groups.

The authors might consider including practical recommendations, such as how clinicians should choose between different IV NSAIDs based on specific surgical scenarios or patient populations.

Phrases like "significant opioid sparing and postoperative pain relief" are repeated in the text and conclusion. Simplify and consolidate these ideas for better flow.

The conclusion should summarize key insights and emphasize future research directions, such as the need for comparative trials to evaluate the relative efficacy and safety of IV NSAIDs.

Author Response

 

Reviewer 3

 

Comment #1

The primary aim of the review should be stated more precisely. For example, mention whether the review focuses on safety, efficacy, or guidelines for the use of IV NSAIDs in surgical settings.

Suggestion: "This narrative review aims to provide an updated evaluation of the efficacy, safety, and clinical use of intravenous NSAIDs for perioperative pain management in adults and children."

 

Response

Thank you for pointing out the need to specify the primary aim more precisely.

 

We have revised our wording in both the Abstract and Introduction to state clearly that our objective is to provide an updated evaluation of the efficacy, safety, and clinical use of IV NSAIDs for perioperative pain management in adults and children.

 

Related revised manuscript text

This narrative review aims to provide an up-to-date evaluation of the efficacy, safety and clinical use of intravenous (IV) NSAIDs for peri-operative pain management in adults and children.

 

The primary objective of the present narrative review is aims to provide an updated evaluation of the efficacy, safety, and clinical use of intravenous NSAIDs for perioperative pain management in adults and children.

 

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Comment #2

Briefly explain why IV NSAIDs are critical in multimodal analgesia, such as their role in reducing opioid dependency and managing inflammation. This provides context for the review.

 

Response

Thank you for highlighting the need to explain why IV NSAIDs are important in multimodal analgesia.

 

We have updated the manuscript to emphasize that IV NSAIDs reduce opioid use and manage inflammation more effectively when combined with other agents. We also cite guidelines from the American Pain Society and the European Society for Paediatric Anaesthesiology that recommend IV NSAIDs as part of an overall strategy for improved perioperative pain control. This expanded discussion provides the context you suggested for understanding the role of IV NSAIDs in multimodal pain management.

 

Related revised manuscript text

The core principle of multimodal postoperative analgesia including paracetamol and/or NSAIDs (in the absence of contraindications, such as patients undergoing coronary artery bypass graft surgery) has been endorsed as a strong recommendation with high-quality evidence by the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. The guideline suggested that IV and oral administrations were similar for pain relief, the onset of action might be faster with IV administration. According to the guidelines published by the European Society for Paediatric Anaesthesiology (EPSA), the consistent intra- and postoperative use of non-opioid drugs (including NSAIDs has an opioid-sparing effect and is a cornerstone of intraoperative pain management. The EPSA recommends (if available) an intravenous paracetamol/NSAID after the induction of anesthesia and throughout the postoperative period for several types of surgery, including limb fracture repair, Nissen fundoplication (open and laparoscopic), thoracoscopy/thoracotomy, appendicectomy, hypospadias repair, and the correction of congenital hip dislocation. The EPSA’s dose level suggestions are 0.5 to 1 mg per kg (up to 30 mg) for a single intraoperative dose and 0.15 to 0.2 mg per kg (up to 10 mg) every 6 h (for no more than 48 h) for ketorolac 1 mg per kg every 8 h for ketoprofen, and 10 mg per kg every 8 h for ibuprofen.

 

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Comment #3

The abstract would benefit from clearer structure by dividing key findings into sections (e.g., "Approved Medications," "Efficacy," and "Safety Considerations"). This improves readability.

 

Response

Thank you for suggesting a more structured approach in the abstract.

 

In Pharmacy journal, it is not customary to use formal subheadings in review article abstracts beyond a concluding statement.

However, we have reorganized the abstract’s text to group findings by topic—approved medications, efficacy, and safety—so the reader can more easily follow our main points. This ensures the key messages remain clear and succinct without requiring separate subheadings.

 

Related revised manuscript text

Overall, IV ibuprofen had a more favorable profile with regard to peri- and postoperative opioid sparing and pain relief. Oral ibuprofen and IV ibuprofen have similar levels of efficacy, although IV ibuprofen has a shorter onset of action and is required in patients who are unable to take oral medications. The frequency of significant adverse events appears to be similar for ibuprofen and paracetamol.

 

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Comment #4

Quantify significant findings where possible. For instance, elaborate on the "opioid sparing" effect by specifying ranges or percentages and their clinical implications.

 

Response

Thank you for emphasizing this need. We have revised Table 1 to provide exact data ranges, p-values, and effect sizes where available. These updates offer a clearer sense of how IV NSAIDs reduce opioid requirements and improve pain control in perioperative settings.

 

Related revised manuscript text

Significant opioid sparing effect in early postoperative period in the ibuprofen group (mean ± SD total fentanyl dose = 3.20 ± 4.49 µg, vs. 9.40 ± 4.49 µg in the placebo group; P < 0.001).

 

Patients on ibuprofen+ paracetamol had lower VAS scores vs. ibuprofen alone on day 3 only 6.7 vs. 4.9, respectively (P < 0.002), together with lower median (range) opioid requirements (20 (5-25) vs. 25 (10-35), respectively; P < 0.001)).

 

Compared with post-op paracetamol, IV ibuprofen resulted in a lower mean ± SD pain score (at 24 h: 1.16 ± 0.79 vs. 0.26 ± 0.44, respectively; P < 0.001) and reduced opioid use (342.33 ± 65.59 vs. 215.66 ± 97.26, respectively) in the first 24 h.

 

24-hour opioid consumption was significantly lower in the ibuprofen group (303.33 ± 132.08 mcq vs. 553.00 ± 257.04 for the placebo; P<0.001). Rescue medication (meperidine) use was lower in the ibuprofen group than in the placebo group (125 mg vs. 350 mg, respectively; P=0.012).

 

IV ibuprofen was associated with significantly less opioid consumption compared with placebo (difference in least-square means [95%CI] = 222.9 [241.4 - 24.2] mg; P = 0.017) and greater pain reduction 8 hours after start of infusion (difference in least-square means [95%CI] = 1.1 [0.2–2.0]; P = 0.013).

 

The pain level was significantly lower in the ibuprofen group than in the paracetamol group (P = 0.004) at 4 h, 24 h (P = 0.019) and 48 h (P = 0.017). Ibuprofen was associated with less opioid use (2.68 ± 2.26, vs. 7.32± 6.68 in the placebo group ; p=0.005).

 

Mean ± SD opioid use was 58% lower in the ibuprofen group (26.3 ± 28.7 mg, vs. 62.5 ± 63.8 mg in the placebo group; P < 0.0001). The pain score was 43% lower in the ibuprofen group (1.7 ± 2.2, vs. 3.0 ± 2.8 in the placebo group; P < 0.0001).

 

Etc.,

 

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Table 1

 

 

 

 

Comment #5

Suggestion: "Systematic reviews and meta-analyses report that intravenous NSAIDs reduce postoperative opioid consumption by approximately 20–60%, improving pain management with fewer opioid-related side effects."

 

Response

Thank you for recommending specific wording about the 20–60% reduction in postoperative opioid use.

 

We have adopted your suggestion in the abstract, clarifying that systematic reviews and meta-analyses demonstrate this notable range of opioid sparing, along with improved pain management and fewer opioid-related side effects.

 

Related revised manuscript text

Systematic reviews and meta-analyses report that intravenous NSAIDs reduce postoperative opioid consumption by approximately 20–60%, improving pain management with fewer opi-oid-related side effects.

 

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Comment #6

Address the limitations of current evidence, such as the lack of head-to-head randomized controlled trials, and how this impacts clinical decision-making.

 

Response

Thank you for highlighting the shortage of head-to-head RCTs comparing different IV NSAIDs. This gap forces clinicians to rely on indirect comparisons and observational data, which can limit the precision of treatment choices. To clarify this limitation, we have added a sentence in the Discussion, that underscores the need for direct comparative trials.

 

Related revised manuscript text

A shortage of head-to-head RCTs comparing different IV NSAIDs limits direct comparisons. Most data come from placebo-controlled or observational studies, which can restrict the accuracy of clinical decision-making. Future trials should assess the comparative efficacy, safety, and cost-effectiveness of various IV NSAIDs in diverse populations.

 

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Comment #7

Expand on the unique challenges of using IV NSAIDs in pediatric patients, such as dosage adjustments, safety concerns, and limited approved options for younger age groups.

 

Response

Thank you for emphasizing the challenges of administering IV NSAIDs to pediatric patients. Our manuscript already touches on dosage adjustments, off-label usage, and the limited approvals for younger populations.

 

To address your comment, we have added a brief introductory summary about the limitations on weight-based dosing and the need for closer monitoring of adverse events.

 

Related revised manuscript text

Children often have variable renal function, protein binding, and metabolic pathways, which can alter NSAID pharmacokinetics. Current labeling restricts IV formulations of some NSAIDs to older children, leaving limited approved options for infants and toddlers. Clinicians must therefore apply weight-based dosing and monitor closely for adverse events. Ongoing research is needed to refine age-specific guidelines and extend licensing to broader pediatric populations.

 

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Comment #8

The authors might consider including practical recommendations, such as how clinicians should choose between different IV NSAIDs based on specific surgical scenarios or patient populations.

 

Response

Thank you for suggesting the inclusion of practical recommendations on how to select specific IV NSAIDs based on various surgical scenarios or patient populations. We appreciate the importance of practical guidance; however, it lies beyond the primary scope of our narrative review. Our paper is not intended to serve as a clinical practice guideline or consensus statement, and several existing guidelines already offer detailed recommendations for different patient groups.

 

In order to maintain the focus and coherence of our review, we have chosen to emphasize the literature-based overview of intravenous NSAIDs, their uses, and key considerations.

 

 

 

 

 

Comment #9

Phrases like "significant opioid sparing and postoperative pain relief" are repeated in the text and conclusion. Simplify and consolidate these ideas for better flow.

 

Response

Thank you for identifying the repetition. We have consolidated references to “opioid sparing and postoperative pain relief” in the abstract and conclusion. This ensures a smoother reading experience while preserving the core finding that IV NSAIDs help reduce opioid use and enhance pain management.

 

Related revised manuscript text

Overall, IV ibuprofen had a more favorable profile with regard to peri- and postoperative opioid sparing and pain relief. Oral ibuprofen and IV ibuprofen have similar levels of efficacy, although IV ibuprofen has a shorter onset of action and is required in patients who are unable to take oral medications. The frequency of significant adverse events appears to be similar for ibuprofen and paracetamol.

 

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Comment #10

The conclusion should summarize key insights and emphasize future research directions, such as the need for comparative trials to evaluate the relative efficacy and safety of IV NSAIDs.

 

Response

Thank you for recommending a clearer summary of key insights and a stronger emphasis on future research needs. As suggested, we have refined the Conclusion and added a “Future Directions” section, highlighting the need for head-to-head trials to compare the relative efficacy and safety of various IV NSAIDs.

 

Related revised manuscript text

Conclusions

Our review of the literature data in various surgical settings indicated that intra-venous NSAIDs are well tolerated usually associated with significant (20–60%) opioid sparing, postoperative pain relief, and fewer side effects. Intravenous formulations of NSAIDs will probably continue to be of value in the multimodal approach to perioperative analgesia and enhanced recovery after surgery. In pediatrics in particular, the choice of medication is limited to ibuprofen at early ages and the oral route is not always feasible; hence, IV formulations of NSAIDs are preferred allies in this setting. Topics for further research should include head-to-head trials of IV NSAIDs. In this respect, the American Pain Society’s Clinical Practice Guideline on acute postoperative pain recommends (i) both RCTs and observational studies that capture real-world data and rare AEs, (ii) the stratification of groups according to the baseline pain level, (iii) standardized outcome measures for pain, function, safety, harms, and patient satisfaction, and (iv) measurement periods extending days and weeks, rather than hours.

 

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I would recommend the revised manuscript for publication.