Perioperative Pain Management in Total Knee Arthroplasty: A Narrative Review of Current Multimodal Analgesia Protocols

Round 1

Reviewer 1 Report (New Reviewer)

The manuscript submitted for review describes the standards of pain management based on the literature on the subject. Compared to the cited sources, this review is cursory and contributes little to the general knowledge of analgesia. The authors discuss the management protocol, paying little attention to the essence of using several drugs in the analgesic multimodality protocol. Some quoted theses are poorly documented, e.g. line 261. Gabapentin is one of the recommended first-line preparations in the fight against neuropathic pain (IASP - International Association for the Study of Pain). When writing about different views – the controversy around gabapentin – it is worth presenting more sources on this subject or specifying the principles of pharmacotherapy, giving arguments for and against.

The discussion of non-opioid analgesics and non-steroidal anti-inflammatory drugs does not sufficiently explain why they may be useful in preventing sensitization and sensitization to inflammatory agents during surgical intervention. The principles of multimodal analgesia are implemented through the use of drugs with different mechanisms of action, i.e. paracetamol that inhibits the perception of pain in the central system, blocks the action of CNS peroxidase on arachidonic acid. Here, there is no peripheral effect on tissue inflammatory factors, therefore acetaminophen and NSAIDs can and should be combined. However, meloxicam and celecoxib are not equal here - COX2 preference or selectivity. The cited works on ketamine and magnesium as N-methyl-D-aspatinate receptor antagonists, concerning the US and Canadian markets, should be commented on. In the European Union, ketamine has limited use due to side effects. Minor editorial inaccuracies:  tab 1 - should be formatted according to the template, correct the description and spaces. Line 100 - are you specifying the VSA abbreviation or do you mean Visual Analogic Scale? (then line 45 - enter the shortcut to use on line 100). Please refer to the current 2007 versions of cited items. In the following years, frequently quoted reviews were updated and supplemented with new reports. Conclusions. The review mentions a broad, multidisciplinary approach to the patient, it is worth mentioning the holistic continuation of patient care after leaving the hospital ward.

Author Response

Point 1: The manuscript submitted for review describes the standards of pain management based on the literature on the subject. Compared to the cited sources, this review is cursory and contributes little to the general knowledge of analgesia.

The authors discuss the management protocol, paying little attention to the essence of using several drugs in the analgesic multimodality protocol.

 

 

Response 1: Our intention was to propose multimodal protocols applicable in each center, concise and modular. The purpose was to provide theoretical bases so that readers can then modulate a protocol suitable for the needs of each surgeon and adaptable for the different surgical techniques or non-pharmacological factors connected to pain. Furthermore, for each drug we have proposed which alternatives or drugs can be associated with it in order to insert practical advice to change clinical practice. We then tried to explain how multimodal therapy also applies to intraoperative therapy with LIA.

 

Point 2: Some quoted theses are poorly documented, e.g. line 261. Gabapentin is one of the recommended first-line preparations in the fight against neuropathic pain (IASP - International Association for the Study of Pain). When writing about different views – the controversy around gabapentin – it is worth presenting more sources on this subject or specifying the principles of pharmacotherapy, giving arguments for and against.

 

 

Response 2: We augmented the discourse to better analyze the role of gabapentin as requested. (line 263)

 

Point 3: The discussion of non-opioid analgesics and non-steroidal anti-inflammatory drugs does not sufficiently explain why they may be useful in preventing sensitization and sensitization to inflammatory agents during surgical intervention. The principles of multimodal analgesia are implemented through the use of drugs with different mechanisms of action, i.e. paracetamol that inhibits the perception of pain in the central system, blocks the action of CNS peroxidase on arachidonic acid. Here, there is no peripheral effect on tissue inflammatory factors, therefore acetaminophen and NSAIDs can and should be combined. However, meloxicam and celecoxib are not equal here - COX2 preference or selectivity

 

 

Response 3: Thank you very much for the useful clarification. The concept is expressed by us in the introduction of the preemptive therapy section

 

Point 4: The cited works on ketamine and magnesium as N-methyl-D-aspatinate receptor antagonists, concerning the US and Canadian markets, should be commented on. In the European Union, ketamine has limited use due to side effects.

 

 

 

Response 4:
We believe ketamine is a useful adjunct to therapy, and have reviewed the cited literature with very recent work by Watson to support this

Point 5: Minor editorial inaccuracies:  tab 1 - should be formatted according to the template, correct the description and spaces. Line 100 - are you specifying the VSA abbreviation or do you mean Visual Analogic Scale? (then line 45 - enter the shortcut to use on line 100).

Please refer to the current 2007 versions of cited items. In the following years, frequently quoted reviews were updated and supplemented with new reports. Conclusions. The review mentions a broad, multidisciplinary approach to the patient, it is worth mentioning the holistic continuation of patient care after leaving the hospital ward.

 

Respond 5: Thanks for the helpful hints, we fixed it as requested.

Reviewer 2 Report (New Reviewer)

Dear Authors,

I am honored by the opportunity to review your article. The topic is interesting and relevant because many patients continue to be dissatisfied despite continued progress in total knee replacements.

The text is well-developed and argued; I have no particular notes to make on it. 

It is necessary to reduce the references to a maximum of 40 as over 80 references for a review is excessive. I suggest you eliminate the less relevant ones and those not strictly related to pain management in total knee replacements. 

In addition, you must write all references in the same format according to the standards required by the Journal.

Once the changes are made, I consider the article suitable for publication. 

Author Response

Point 1: I am honored by the opportunity to review your article. The topic is interesting and relevant because many patients continue to be dissatisfied despite continued progress in total knee replacements.

The text is well-developed and argued; I have no particular notes to make on it. 

It is necessary to reduce the references to a maximum of 40 as over 80 references for a review is excessive. I suggest you eliminate the less relevant ones and those not strictly related to pain management in total knee replacements. 

In addition, you must write all references in the same format according to the standards required by the Journal.

Once the changes are made, I consider the article suitable for publication. 

 

 

Response 1:

 

Thank you for your advice and support at work. We have corrected the citations and removed some that were superfluous. However, we are not sure that removing half of the citations is useful, as advised by other reviewers it is necessary that there is a complete state of the art of the recent literature.

Reviewer 3 Report (New Reviewer)

Dear Authors,

Pain management is a hot topic nowadays and this is highlighted in your paper. Lack of protocols is a major problem with a really complex solution due to multifactorial nature of pain and unique demands of every patient and surgery. Your effort is really good, but it would be even better if you had recommended a full protocol of pain management. The novelty of this manuscript is focused on the potentiality a surgeon adopting these guidelines to his everyday practice. However, it is not clear if he could use all of them or which combination is better. 

In addition to, I would like to raise your attention to some other minor problems:

Line 12: There is no synthesis of protocols throughout the manuscript, just simple report of current literature.

Lines 24-25: The written are totally irrelevant and different of the reference you mentioned. Hardy et al. focused on patients with high anxiety levels prior the surgery.  This fault could raise ethical concerns for the whole of the manuscript. 

Line 21: I would like a limited introduction to why pain management is important and which factors contribute to its complexity.

 

Author Response

Point 1:  Pain management is a hot topic nowadays and this is highlighted in your paper. Lack of protocols is a major problem with a really complex solution due to multifactorial nature of pain and unique demands of every patient and surgery. Your effort is really good, but it would be even better if you had recommended a full protocol of pain management. The novelty of this manuscript is focused on the potentiality a surgeon adopting these guidelines to his everyday practice. However, it is not clear if he could use all of them or which combination is better. 

In addition to, I would like to raise your attention to some other minor problems:

 

 

Response 1:

 

Thank you for your advice and support at work. We have properly revised the citation to Hardy's work as requested and completed the introduction as recommended. (line 30

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The authors aimed  to provide a brief and practical synthesis on current multimodal pre-post-surgery analgesia protocols for primary TKA (excluding intraoperative anaesthetic techniques) reported especially in recent meta-analysis and reviews. The focus was not only on the traditional aims (pain scores and opioid sparing), but also to the functional recovery and patient-reported outcomes. The issue is  important, however authors must add to the text some table/figures in supporting this review.

Author Response

We thank you for the time and attention you paid in revising our manuscript.  The manuscript was reviewed by a native speaker. we corrected the text as requested, finding his advice and observations very useful.

Author Response File: Author Response.pdf

Reviewer 2 Report

Dear Editor, dear colleagues!
Thanks for allowing me to review the manuscript of Franzoni et al., who submitted a review about pain management in total knee athroplasty. Before diving into the manuscript, I'd like to declare that I don't have any conflict of interest.

The manuscript is well structured and easy to read. Nevertheless, I do have many concerns since the manuscript seems more to be in the "middle of the road" and not ready for publication. I hope that the following comments will help you to improve your project and your communication.

1) Your manuscript relies on a hypothesis that you mentioned in your abstract with "Since there is no consensus on the optimal perioperative analgesic method[...]". How do you define "optimal"? I do not agree with the authors that there is no consensus or only little evidence with regards to pain management in TKA. TKA is a very frequently performed operation in many countries. Therefore, it has been addressed pain-wise in a lot of publications. A very often cited and popular one is the review by Fischer et al. 2008 (Pubmed id: 18627367), which you completely miss. Particularly within the last decade, many organizations have contributed to a growing evidence in the field of pain management. The PROSPECT guidelines are probably the most popular one since they include a lot of evidence. You mentioned the 2022 version as your reference no 18, but only in the paragraph of local anaesthetics. However, it clearly shows that your hypothesis is wrong.

As a consequence, it is not clear to me what your article adds to the reader's knowledge. If one reads your references no 1 and 18, she*he will have a better understanding of the topic than with your review.

2) This also comes with the question of who should be the target reader of your manuscript? On the one hand, you stated "excluding intraoperative anaesthetic techniques" in your abstract. So it is not intended for anaesthesiologists, is it? Then, why don't you discuss any surgical techniques which potentially influence the "amount" of postoperative pain? E.g., torniquet, time, expertise, early mobilization....? On the other hand, you talk about anaesthesia techniques like neuraxial anaesthesia or peripheral nerve blocks. Why is a PNB a common "orthopaedic practice" (line 148)? Do orthopaedics perform the nerve blocks in your department? In most countries, it is obvious that regional anaesthesia is performed by anaesthesiologists.

3) Throughout your manuscript, you do a lot of statements without having any citations (n>30). This is an absolutely must to improve, as the status quo does not fulfill the requirements of good scientific writing. It is definitely not enough to collect all references at the end of a paragraph.

4) Many hospitals do have special acute pain services. Why don't you discuss the advantages of such specialized stuff, rather than concluding that "pain control after TKA remains a challenge"? There is a lot of evidence regarding this topic, showing that it is not "a challenge", but achievable with some efforts.

5) What about combinations of local anaesthetics, contraindications? Ischiadic nerve blocks? Combinations of peripheral nerve blocks to have more benefits?

6) Spelling errors: Please refer to a language improvement service. For example, I miss a lot of commas in the text, e.g., at lines 23, 63, 209, 329. You also misuse some adjectives with adverbs, e.g., at lines 26, 232. Further, delete the space in line 86. At line 31, the sentence "97% patients" is incorrect. At line 330, "update guidelines" is incorrect.

7) Specify the type of the article in your title by adding "- a narrative review". Please compare the number of references of your manuscript to other reviews. You'll notice that reviews usually have many more references.

8) A review should compare the given literature with possible advantages and disadvantages and not only list information that can be found in a textbook too. Why don't you discuss, e.g., if more or less Acetaminphen is better? This also applies to all your drug recommendations.

9) Minor points: What do you mean by "(comorbidities)" at line 36 at this position? The following words also contribute to comorbidities. Multimodal analgesia is part of the WHO analgesia scheme and not only introducet by Kehlet (the article is about balanced anaesthesia). Gabapentin is not an opioid, underline it at line 252 to show the reader that you left the discussion of opioids.

Author Response

We thank you for the time and attention you paid in revising our manuscript.  The manuscript was reviewed by a native speaker. we corrected the text as requested, finding his advice and observations very useful.

Author Response File: Author Response.pdf

Reviewer 3 Report

This is a narrative review (the authors don't use this term but that's what it is) of recent meta-analyses and systematic reviews that address perioperative pharmacotherapy for acute pain management in total knee arthroplasty. The manuscript is well-written and referenced. The following comments are offered in order to strengthen an already robust and succinct presentation and treatment of this important perioperative subject.

Title: The title needs a qualifying statement because as written, it implies a universal definitive approach is known and practiced. Consider adding ": A narrative review of current multimodal analgesia protocols" or ": A summary of recent reviews."

Abstract: very brief. Consider adding a couple of sentences summarizing the agents and multimodality.

Keywords: consider adding "opioid", "NSAID", and "multimodal." Keep the others.

Introduction: do not capitalize a drug name unless it begins a sentence. Insert a space between the number and the unit (i.e., 100 mg not 100mg.)

Pain caused by TKA surgery is often acute-on-chronic because patients often have chronic pain due to joint debilitation with treatments prior to surgery, some of which are on an opioid "backbone." The authors should add and discuss these two related points in the introduction.  Patients on opioids preoperatively present a more challenging clinical scenario. You discuss it in section 6 but it should be introduced earlier.

There is no methods section that describes how the citations were selected and reviewed.

Preemptive analgesia:

line 102: a dose range with a reference should be added for gabapentin as well as the cautious use in the elderly and those with renal impairment. I think there is a recent Cochrane Review.

Line 108: if the patient is already on opioids, they should be continued and then weaned postoperatively. Probably best achieved through a pain service that includes a clinical pharmacist. The best and most recent systematic review is Wang MC, Harrop JS, Bisson EF, Dhall S, Dimar J, Mohamed B, Mummaneni PV, Hoh DJ. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Perioperative Spine: Preoperative Opioid Evaluation. Neurosurgery. 2021 Oct 13;89(Suppl 1):S1-S8. doi: 10.1093/neuros/nyab315. 

Local anesthetics:

Line 126: consider adding a table with ester and amide anesthetics used in clinical practice with relative potencies, maximum cumulative doses, and kinetic (half-life) parameters. Might want to mention LAST and its treatment briefly.

Systemic analgesics:

Line 189: the dose regimen is correct. Consider lowering the maximum daily amount from 4 g to 3 g based on J&J recommendations. The makers of TYLENOL® in 2011 lowered the maximum daily dose for single-ingredient Extra Strength TYLENOL® (acetaminophen) products sold in the U.S. from 8 pills per day (4,000 mg) to 6 pills per day (3,000 mg). The dosing interval has also changed from 2 tablets every 4–6 hours to 2 tablets every 6 hours. See https://www.tylenol.com/safety-dosing/dosage-for-adults for more information.

Line 217: consider adding a statement about monitoring opioids using morphine milligram equivalents (MME), especially when changing from one to another. Opioid risk should also be conducted. See https://nida.nih.gov/sites/default/files/opioidrisktool.pdf. In addition, patients on opioids should not be taking benzodiazepines. If discharged on opioids, patients should receive a co-prescription of nasal naloxone if MME is greater than 50 mg per day.

 

Author Response

We thank you for the time and attention you paid in revising our manuscript.  The manuscript was reviewed by a native speaker. we corrected the text as requested, finding his advice and observations very useful.

Author Response File: Author Response.pdf

Reviewer 4 Report

I did not complete a review of this manuscript as the English was very poorly written and I could not get past the first page. 

Round 2

Reviewer 2 Report

Dear authors,

many thanks for your revised version, I can see a clear step forward in the quality of your manuscript. I like that you changed your title, your text underwent a language improvement, and in particular that your citations are now stated correctly. As we can see, the number of your references increased from 39 to 79, which is definitely a more appropriate number for a review.

Nevertheless, there are still many points which have not been addressed. For example, if you say your manuscript is about postoperative pain control procedures (your answer to my comment no 3), why don't you discuss e.g., early mobilization (overall, not only at local anesthetics)? You still consider PNB an orthopaedic practice (now line 154, former 141). Gabapentins and Dexamethasone are still in the paragraph of opioids because of missing underline. Why didn't you discuss the dosages of drugs as suggested? Why didn't you discuss the combinations of local anesthetics as suggested? You state that you clarified and corrected, but you did not. I also miss reference no 80 from your new Table 1.

Furthermore, and probably the most important aspect, why did you delete the reference of Lavand'homme et al., who published the PROSPECT guidelines of pain management in TKA? This is one of the main sources of evicende of pain management in TKA, so rather than deleting this citation you should discuss it, figure out the strengths and weaknesses, and in a narrative review it is also allowed to state your personal opinion. You also deleted the former reference no 1, but exactly these two reference were those which I considered the most important. By deleting them, you give the impression that you do not want them to show up so you do not need to discuss them. This is unsatisfying.

I think most of these points occurred because you did not properly respond to Reviewer's comments point by point but only copied "We thank you for the revision; we have corrected the text to clarify." to each point raised. In some cases, however, you did not even correct the text. I strongly recommend that you address each single sentence of a Reviewer in your future works. You do not need to agree to everything what they will say as Reviewers might also be wrong :) . But you should discuss every point. And most important, do not ignore it.

Author Response

1: We greatly appreciate your comment, thanks to your helpful advice we have worked to provide work suitable for publication.

2. We fully agree that early mobilization is a cornerstone of postoperative patient management. We excluded it from our discussion to focus on multimodal pain treatment, we found it confusing to discuss fast track protocol as well.

3. We have corrected the discussion on the use of BNP: it is an anesthesiological practice, useful in orthopedic surgery

4. Thanks for the tip, we've rearranged the paragraphing for Gabapentins and Dexamethasone.

5. Our goal was to explain what for us is a multimodal therapy, giving a clear general picture, we felt that analyzing the different combinations or the many dosing algorithms in the literature could create confusion.

6. We have reintroduced the reference on prospect. We are sorry for the mistake.