Volume 27 Number 2

Key messages

• The efficacy of systemic analgesics for painful chronic wounds has not been clinically evaluated to date.
• Nonsteroidal anti-inflammatory drugs must reach the site of inflammation to produce their analgesic effect.
• The risk-benefit balance of nonsteroidal anti-inflammatory drugs on ischemic wounds remains to be evaluated.

Background

This article expands on the ideas presented in a previous commentary¹ to the EWMA guideline on the holistic management of wound pain.² The current document primarily expresses the author’s ideas and opinions on how to use basic pharmacokinetic knowledge to guide the treatment of the nociceptive component of painful chronic wounds with nonsteroidal anti-inflammatory drugs (NSAIDs) after assuming that clinical trials are lacking.

Painful chronic wounds: a major health issue

Chronic wounds can cause a variety of symptoms in patients, such as pain, itching, unpleasant odor, depression, social isolation and others. But among them, patients often report pain as the worst symptom, the one that most impairs their quality of life,^3-6 sometimes to the point of considering suicide.^7,8

Currently, there are several guidelines available from scientific societies dedicated to chronic wounds that address the analgesic treatment of painful chronic wounds.^2,9-11 Analgesic treatment is traditionally divided into local analgesics-anesthetics, and systemic analgesics. The author is unaware of any comparative clinical study determining which of these alternatives is superior. However, it is clear that, from a pharmacokinetic perspective, the topical approach offers numerous advantages over the systemic approach.^12-14

Topical analgesics: A priori, the best pharmacokinetic alternative

First, topical application allows analgesic efficacy to be prioritised, as the drug is applied directly to the painful area,¹² avoiding the processes of distribution and diffusion throughout the body to the painful site.

Second, it is very easy to apply the desired medication to the wound.¹²

Third, it allows for greater control of the treatment, as the dose can be adjusted and, depending on the formulation, any excess dose could be removed if desired.¹²

Fourth, topical application increases systemic safety. Topical doses are usually lower than doses required systemically because distribution and diffusion processes are avoided, as stated. Additionally, the rate of absorption from the wound into the systemic circulation may be reduced due to impaired blood perfusion to the wound. For all these reasons, the risk of developing systemic adverse effects is lower with topical application than with systemic administration.^12,13

Fifth, the risk of clinically relevant pharmacokinetic and pharmacodynamic interactions is significantly reduced.^12,13 Most patients with chronic wounds are frail elderly individuals taking multiple medications, and adding systemic analgesics exposes them to an increased risk of adverse effects secondary to drug interactions.¹⁴ This risk is especially important in the case of NSAIDs due to the large number of dangerous interactions they can cause.¹⁵ This issue reinforces the safety of topical administration over systemic administration.

Despite these obvious advantages inherent to the topical route, the number of drugs that have been studied in controlled clinical trials and approved for the topical analgesic treatment of painful wounds is very small.¹⁶ Alternatives are limited to eutectic lidocaine and prilocaine cream, and dressings impregnated with the nonsteroidal anti-inflammatory drug ibuprofen,¹⁶ although there is some controversy regarding the efficacy of the latter.^17,18 Additionally, there is also some controversy regarding the effectiveness of topical use of other families of systemic analgesics, such as opioids.^16,18

Although this article aims to focus on systemic treatment, the author would like to express a final reflection on topical treatment before moving forward. Clinical trials are very expensive and beyond the reach of most healthcare professionals. For this reason, the number of topical analgesics reported in publications other than clinical trials, such as case reports, case series, retrospective studies, etcetera, is much higher. Without attempting to be exhaustive, these drugs include cannabinoids¹⁹, gabapentinoids, ketamine, local anesthetics other than lidocaine and prilocaine,²⁰ sevoflurane,²¹ metamizole,²² etcetera. While clinical trials with these drugs are conducted, if they are conducted at all, these and other alternatives may be an option to consider for off-label use when approved options prove ineffective.²³

Systemic analgesics: two questions to be solved

Returning to the guidelines for the treatment of chronic wounds, there are numerous examples of guidelines promoted by scientific societies in which pain is not even taken into account.^24-30 Some of the guidelines that do take pain into account offer simple, not very useful recommendations,^17,31,32 while the rest of the guidelines consulted by the author agree on the recommendation to follow the steps of the WHO analgesic ladder.^2,9-11 As previously stated, the author has already expressed concern that recommending the WHO analgesic ladder for the treatment of painful chronic wounds would constitute a kind of misappropriation.¹

The first step of the WHO ladder includes common analgesics, such as aspirin, while the second and third steps include minor and major opioids.³³ The guidelines cited recommend always follow the steps of this ladder,^2,9-11 regardless of the type of wound, etiology or perfusion status. From the author’s perspective, two specific problems arise. The first concerns the lack of evidence, the lack of clinical trials or any other type of clinical study to support the recommendation of treating chronic wounds according to the WHO ladder. The second relates to pharmacokinetics, in particular the use of NSAIDs without distinguishing between well- and poorly perfused wounds.

Systemic analgesics for painful wounds: lack of clinical studies

As stated, all guidelines recommending the treatment of painful chronic wounds with systemic analgesics refer to the WHO analgesic ladder.^2,9-11 However, there are no clinical studies to support this recommendation. Astonished readers can verify this statement by consulting the most common databases.

Assuming the lack of studies is true, the question arises as to why the guidelines recommend the WHO analgesic ladder. As far as the author has been able to investigate, the key moment was the publication in 1999 of a review on the state of analgesic treatment for painful wounds by nurse Susan Senecal.³⁴ Unable to find any studies, this nurse sensibly suggested the possibility of using the WHO analgesic ladder, which at that time had just released its second expanded version.³⁵ However, what Susan Senecal proposed as a suggestion was later reproduced in a guide as this nurse had applied the WHO analgesic ladder to the treatment of chronic wounds.³⁶ Since then, the WHO ladder has been recommended in the other guidelines cited.^2,9-11 This is the most plausible explanation the author has been able to find to explain why evidence-based guidelines make a recommendation that is not based on clinical studies.

What to do when evidence is lacking?

When dealing with a clinical problem for which clinical studies are lacking, proponents of evidence-based medicine recommend descending the evidence pyramid until reaching some level of evidence.³⁷ Such a level could be personal clinical experiences or, failing that, going further down the pyramid to basic science.³⁸ The guideline for pain management in epidermolysis bullosa represents a very interesting example of how to take clinical experience into account when no studies are available. Most of the recommendations are based on the opinion of experts and patients’ relatives.³⁹ As for descending the pyramid to the level of basic science, this would be the case for the use of NSAIDs in painful chronic wounds since, in the absence of clinical studies, pharmacokinetic knowledge would be the best available evidence.

Pharmacokinetic-guided treatment with NSAIDs for chronic wounds

By following the WHO ladder, all patients with painful chronic wounds should be treated with first-line analgesics, which are paracetamol and NSAIDs³⁵ — and also metamizole in those countries where it is approved,¹⁰ — regardless of the degree of ischemia in the wound. From a pharmacokinetic point of view, this generalisation does not pose any problems for centrally acting drugs, such as paracetamol or metamizole, because their clinical efficacy should be independent of the degree of perfusion/ischemia of the wound. However, it can be a problem for analgesics that act predominantly at a peripherical level, like NSAIDs.

Although NSAIDs have been found to exert a certain pain-modulating effect at the central level, the fundamental analgesic mechanism of action derives from the inhibition of the cyclooxygenase enzyme (COX),^40,41 meaning that most of the clinical effect occurs primarily at the peripheral level in damaged tissues.

Two isoforms of COX have been fully identified, which have been named COX-1 and COX-2 (Figure 1).

 

Figure 1. The analgesic mechanism of action of NSAIDs involves the inhibition of COX-2, while the inhibition of COX-1 produces unwanted effects. Illustration created by the author.

 

COX-1 is the constitutive isoform and is always present in organs such as the kidneys, the gastrointestinal tract and platelets. This isoform has cytoprotective effects, which is why the inhibition of COX-1 by NSAIDs causes, in addition to a mild analgesic effect, the well-known systemic adverse effects of these drugs, such as bleeding, kidney failure or gastrointestinal ulcers.^40,42 Since COX-1 is always present, a patient taking NSAIDs for any reason will always be at risk of developing these adverse effects. To compensate for this risk and increase the likelihood of achieving a favorable risk-benefit balance, the probability of achieving efficacy must be high.

COX-2 is the inducible isoform, meaning that it is normally undetectable in most tissues, but its expression increases and appears at the site of inflammation when tissues are damaged. After cell death, arachidonic acid is generated from the components of cell membranes. Arachidonic acid is in turn metabolised by COX-2 to produce prostaglandins, which are responsible for the chain of events that lead to inflammation and pain.⁴⁰ Overall, the beneficial anti-inflammatory and analgesic effects of NSAIDs are due to the sum of the inhibition of both COX-1 and COX-2 isoforms, the latter both centrally and peripherally.⁴³ However, the primary analgesic mechanism is the inhibition of COX-2 at the inflammatory focus⁴¹ (Figure 1). And since COX-2 appears in the inflammatory focus (Figure 2), NSAIDs must reach the inflammatory site to elicit most of their analgesic effect.

 

Figure 2. The COX-2 isoform is induced at the site of inflammation. Image generated by the author with DALL-E.

 

This will not be a problem in well-perfused wounds with a significant inflammatory component, such as pyoderma gangrenosum, because NSAIDs will be able to adequately achieve their pharmacological target. However, it may be a problem in wounds where blood perfusion is compromised, such as arteriolosclerotic wounds or pressure ulcers, as the likelihood of NSAIDs producing beneficial effects would be reduced without diminishing their ability to cause adverse effects. Theoretically, the risk-benefit balance would be unfavorable (Figure 3). For this reason, the likelihood of NSAIDs having a beneficial effect on chronic wounds would be inversely proportional to the severity of the ischemic component of the wound.

 

Figure 3. Risk-benefit balance of NSAIDs treatment for well and poorly perfused chronic wounds. Illustration created by the author.

 

The theory that drug delivery is reduced in ischemic ulcers is based on solid pharmacokinetic knowledge, but it remains to be proven. The best way to assess the accuracy of this theory would be to compare drug concentrations in the wound bed between ischemic and non-ischemic wounds. However, the author is not aware of any studies in which NSAIDs levels were measured, or any studies that compared the levels of any drug between ischemic and non-ischemic wounds. Micro dialysis techniques would allow such measurements to be made. In fact antibiotic levels have been measured in infected diabetic foot wounds, for example.⁴⁴ Antibiotics were probably measured rather than NSAIDs because treatment failure in infected wounds has a more significant clinical impact than failure to treat painful wounds.

The corollary of the theory is that, for equal doses of NSAIDs, patients with poorly perfused wounds will experience more pain than patients with better perfused wounds. The accuracy of this corollary could be assessed by reviewing comparative clinical studies on the use of NSAIDs in wounds with and without an ischemic component, but again, there are no studies on this particular topic either.

A common misconception: “Drug inside the body” does not equal “Treatment accomplished”

This section is dedicated to emphasising a common misconception, which is believing that a drug always achieves the desired effect once it is administered to a patient. Among the various factors that can modulate the clinical effect of a drug, we will focus here on a very obvious one: a drug must achieve its pharmacological target to be effective. This statement will be reinforced by examining two life-threatening scenarios in which treatment failure could be fatal for the patient, because they involve the eradication of bacteria and cancer cells from the organism.

The first example involves poor diffusion of drugs from the blood to the target organ or tissue due to the existence of barriers, such as daptomycin and the blood-brain barrier. After systemic administration, daptomycin concentrations in the cerebrospinal fluid are low, which would significantly reduce the likelihood of successfully treating central nervous system infections. This well-known pharmacokinetic issue makes daptomycin unsuitable as a first-line agent for treating central nervous system infections, even when the causative agent is fully susceptible to daptomycin.⁴⁵ Any physician who ignores this basic knowledge would be making a serious mistake by treating bacterial meningitis exclusively with daptomycin at usual doses, believing that the treatment would be successful just by administering the antibiotic. In fact, treatment of bacterial meningitis with daptomycin frequently involves intrathecal administration of the antibiotic.⁴⁶ This technique, although invasive, makes it possible to overcome poor diffusion from blood without using higher doses.

Leaving barriers aside, the second example refers to situations in which drugs cannot adequately reach their target due to poor blood perfusion, increasing the likelihood of therapeutic failure. Selective regional drug delivery directly into the artery supplying the site of interest can overcome the problem of the reduced amount of systemic drugs reaching their target due to hypoperfusion. This method of administration is generally reserved for life-threatening conditions because it is an invasive technique that requires the placement of an arterial catheter. Septic shock caused by bacterial peritonitis is a life-threating condition.⁴⁷ As such, selective regional administration of antibiotics directly through the mesenteric artery to increase the amount of antibiotics reaching the infectious site has been reported.⁴⁸ Examples of selective regional drug delivery also come from the oncological field.⁴⁹ Exceptionally, examples also come from the field of infected chronic wounds. Twenty-five patients with infected diabetic foot wounds were successfully treated with selective intra-arterial administration of medications, including antibiotics.⁵⁰

Overall, these examples reinforce the importance of organ perfusion status for drugs to exert their effect, and also the hypothesis that the efficacy of NSAIDs may be reduced in ischemic wounds because they do not reach the inflammatory focus in adequate doses.

Future solutions: integrating pharmacokinetics, technology and common sense while waiting for clinical trials

The key idea guiding this document is that there is an unfavorable balance when using systemic NSAIDs for the analgesic treatment of painful chronic wounds of ischemic etiology, but no clinical evidence is provided to support this claim. The best evidence would be provided by a clinical trial. Pharmaceutical companies are in a strong position to conduct such trials, but they may lack incentives to run trials in which old, cheap drugs are involved.

Determining clinically the degree of wound perfusion can be a very difficult challenge. Fortunately, some new technologies can assist in decision-making. Several advanced devices are currently used to estimate blood perfusion in chronic wound beds, which likely allow for a more accurate assessment than traditional clinical judgment. Newer noninvasive technologies incorporate principles from imaging, spectroscopy and tissue oxygen measurement.⁵¹ They could be useful to determine the degree of blood perfusion in wounds and to classify them according to this characteristic⁵² (Figure 4). These new techniques could help determine which wounds are more or less susceptible to treatment with peripherally acting drugs such as NSAIDs.

 

Figure 4. Noninvasive measurement of oxygen saturation could help to distinguish between wounds that are well perfused (upper panel: red and yellow colors predominate in a venous ulcer) and poorly perfused (lower panel: blue and green colors predominate in an ischemic ulcer related to antiphospholipid syndrome). Courtesy of Miguel Ángel Mellado-Sanz (HERIDEA).

 

While clinical trials are conducted, if they ever are, and in the absence of new technologies in the workplace, what attitude should the average healthcare professional dealing with chronic wounds maintain? In the author’s opinion, the most sensible and logical clinical approach would be to conduct individual therapeutic trials, meaning prescribe an NSAID for a painful wound, re-evaluate the analgesic effect after a day or two and, if it proves ineffective, discontinue it to avoid unwanted effects.

Additionally, from a scientific perspective, regular health workers should report case series or retrospective comparative studies that include real-world data, which is what most of us can achieve within the pyramid of evidence. Furthermore, I would also recommend expanding these studies beyond NSAIDs to include other systemic analgesics, such as paracetamol and metamizole. Finally, these studies should differentiate between types of chronic wounds. Overall, we need to assess the risk-benefit profile of each specific systemic analgesic for each type of chronic wound.

Conclusion

Overall, the systemic treatment of painful chronic wounds warrants further study. With regard to drugs that act on the inflammatory focus, such as NSAIDs, clinical studies should differentiate between different types of wounds based on their degree of perfusion. New technologies can greatly assist in guiding treatment by helping to distinguish between well- and poorly perfused wounds.

Acknowledgements

I want to express my gratitude to Samantha L. Holloway and Professor Andrea Pokorná for encouraging me to write this paper, and also to Miguel Ángel Mellado-Sanz (HERIDEA) for kindly providing images from his own stock archive.

Conflict of Interest

The author declares no conflict of interest.

Funding

The author received no funding for this study.

Author(s)

Manuel Gerónimo-Pardo PhD
Department of Anesthesiology, Gerencia de Atención Integrada de Albacete [Integrated Care Management of Albacete], Spain
Sociedad Española de Heridas [Spanish Society of Wounds] and Director of the journal Heridas y Cicatrización [Wounds and Healing], Spain

Email mgeronimop@sescam.jccm.es

References

1. Gerónimo-Pardo M. The misappropriation of the WHO analgesic ladder for painful chronic wounds: from repair to retirement? J Wound Manag. 2024;25(3):114–116. doi:10.35279/jowm2024.25.03.07
2. Holloway S, Ahmajärvi K, Frescos N, Jenkins S, Oropallo A, Slezáková S, Pokorná A. Holistic management of wound-related pain. J Wound Manag. 2024;25(1,Sup1):S1–84. doi:10.35279/jowm2024.25.01.sup01
3. Taverner T, Closs J, Briggs M. A meta-synthesis of research on leg ulceration and neuropathic pain component and sequelae. Br J Nurs. 2011;20(20):S18,S20,S22-27. doi:10.12968/bjon.2011.20.Sup12.S18
4. Taverner T, Closs J, Briggs M. The journey to chronic pain: a grounded theory of older adults’ experiences of pain associated with leg ulceration. Pain Manag Nurs. 2014;15(1):186–198. doi:10.1016/j.pmn.2012.08.002
5. Guarnera G, Tinelli G, Abeni D, Di Pietro C, Sampogna F, Tabolli S. Pain and quality of life in patients with vascular leg ulcers: an Italian multicentre study. J Wound Care. 2007;16(8):347–351. doi:10.12968/jowc.2007.16.8.27856
6. Newbern S. Identifying pain and effects on quality of life from chronic wounds secondary to lower-extremity vascular disease: an integrative review. Adv Skin Wound Care. 2018;31(3):102–108. doi:10.1097/01.ASW.0000530069.82749.e5
7. Carter AC, Nicholas JJ. The importance of the complete history in the discovery of a potential suicide: a case report. Arch Phys Med Rehabil. 2003;84(3):460–461. doi:10.1053/apmr.2003.50000
8. Fernández Ginés FD, Cortiñas Sáenz M, Selva Sevilla C, Gerónimo Pardo M. Sevoflurane topical analgesia for intractable pain with suicidal ideation. BMJ Support Palliat Care. 2022;12(e2):e192–193. doi:10.1136/bmjspcare-2019-002023
9. Hasegawa M, Inoue Y, Keneko S, Kanoh H, Shintani Y, Tsujita J, et al. Wound, pressure ulcer and burn guidelines – 1: Guidelines for wounds in general, 2nd ed. J Dermatol. 2020;47(8):807–833. doi:10.1111/1346-8138.15401
10. Perdomo Pérez E, de Haro Fernández F, Gaztelu Valdés V, Ibar Moncasi P, Linares Herrera P, Pérez Rodríguez MF. El dolor en las heridas. Serie Documentos Técnicos GNEAUPP nº VI. Grupo Nacional para el Estudio y Asesoramiento en Úlceras por Presión y Heridas Crónicas [Pain in wounds. GNEAUPP Technical Documents Series No. VI. National Group for the Study and Advice on Pressure Ulcers and Chronic Wounds]. Logroño; 2021.
11. Eriksson E, Liu PY, Schultz GS, Martins-Green MM, Tanaka R, Weir D, et al. Chronic wounds: Treatment consensus. Wound Repair Regen. 2022;30(2):156–171. doi:10.1111/wrr.12994
12. Choi E, Nahm FS, Han WK, Lee PB, Jo J. Topical agents: a thoughtful choice for multimodal analgesia. Korean J Anesthesiol. 2020;73(5):384–393. doi:10.4097/kja.20357
13. Mervis JS, Federman DG. Pain management in patients with chronic wounds. Curr Derm Rep. 2018;7:136–146. doi:10.1007/s13671-018-0220-2
14. Dubský M, Fejfarova V, Bem R, Jude EB. Pain management in older adults with chronic wounds. Drugs Aging. 2022;39(8):619–629. doi:0.1007/s40266-022-00963-w
15. Verbeeck RK. Pharmacokinetic drug interactions with nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet. 1990;19(1):44–66. doi:10.2165/00003088-199019010-00004
16. Purcell A, Buckley T, King J, Moyle W, Marshall A. Topical analgesic and local anesthetic agents for pain associated with chronic leg ulcers: A systematic review. Adv Skin Wound Care. 2020;33(5):240-251. doi:10.1097/01.ASW.0000658572.14692.fb
17. Neumann HAM, Cornu-Thénard A, Jünger M, Mosti G, Munte K, Partsch H, et al. Evidence-based (S3) guidelines for diagnostics and treatment of venous leg ulcers. J Eur Acad Dermatol Venereol. 2016;30(11):1843–1875.doi:10.1111/jdv.13848
18. Ffrench C, Finn D, Velligna A, Ivory J, Healy C, Butler K, et al. Systematic review of topical interventions for the management of pain in chronic wounds. Pain Rep. 2023;8(5):e1073. doi:10.1097/PR9.0000000000001073 Erratum in: Pain Rep. 2023;8(6):e1105. doi:10.1097/PR9.0000000000001105
19. Healy CR, Gethin G, Pandit A, Finn DP. Chronic wound-related pain, wound healing and the therapeutic potential of cannabinoids and endocannabinoid system modulation. Biomed Pharmacother. 2023;168:115714. doi:10.1016/j.biopha.2023.115714
20. Tayeb BO, Winegarden JA, Alashari RA, Alasmari M, Winegarden J, Boker F, et al. Scoping review of off-label topical analgesia in palliative, hospice and cancer care: towards flexibility in evidence-based medicine. J Pain Res. 2021;14:3003-3009. doi:10.2147/JPR.S263845
21. Gerónimo-Pardo M. Sevoflurane: Features and uses in topical application for wound care. In: Rajendram R, Patel VB, Preedy VR, Marti CR, eds. Treatments, Mechanisms, and Adverse Reactions of Anesthetics and Analgesics. The Neuroscience of Pain, Anesthetics, and Analgesics. Academic Press; 2022, pp. 165–179 doi:10.1016/B978-0-12-820237-1.00017-X
22. Nieto-Carrilero R, Ballesteros-Ortega MD, Domingo-Chiva E, Gerónimo-Pardo M. Topical metamizole as an off-label analgesic to treat painful ulcers secondary to arteriolosclerosis [Spanish]. Case report. Heridas y Cicatrización [Wounds and Healing].2023;13(2):6–11.
23. Padilla del Rey ML, Gerónimo-Pardo M, García Fernández MR, Cartagena Sevilla J. Painful diabetic foot ulcer amputation avoided thanks to topical sevoflurane [Spanish]. Rev Soc Esp Dolor. 2018;26(4):253. doi:10.20986/resed.2018.3683/2018
24. Robson MC, Cooper DM, Aslam R, Gould LJ, Harding KG, Margolis DJ, et al. Guidelines for the treatment of venous ulcers. Wound Repair Regen. 2006;14(6):649–662. doi:10.1111/j.1524-475X.2006.00174.x
25. Steed DL, Attinger C, Colaizzi T, Crossland M, Franz M, Harkless L, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680–692. doi:10.1111/j.1524-475X.2006.00176.x
26. Whitney JA, Phillips L, Aslam R, Barbul A, Gottrup F, Gould L, et al. Guidelines for the treatment of pressure ulcers. Wound Repair Regen. 2006;14(6):663–679. doi:10.1111/j.1524-475X.2006.00175.x
27. Marston W, Tang J, Kirsner RS, Ennis W. Wound Healing Society 2015 update on guidelines for venous ulcers. Wound Repair Regen. 2016;24(1):136–144. doi:10.1111/wrr.12394
28. Lavery LA, Davis KE, Berriman SJ, Braun L, Nichols A, Kim PJ, et al. WHS guidelines update: Diabetic foot ulcer treatment guidelines. Wound Repair Regen. 2016;24(1):112–126. doi:10.1111/wrr.12391
29. Gould L, Stuntz M, Giovannelli M, Ahmad A, Aslam R, Mullen-Fortino M, et al. Wound Healing Society 2015 update on guidelines for pressure ulcers. Wound Repair Regen. 2016;24(1):145–162. doi:10.1111/wrr.12396
30. Atkin L, Bućko Z, Conde Montero E, Cutting K, Moffatt C, Probst A, et al. Implementing TIMERS: the race against hard-to-heal wounds. J Wound Care. 2019;23(Sup3a):S1–50. doi:10.12968/jowc.2019.28.Sup3a.S1
31. Hopf HW, Ueno C, Aslam R, Burnand K, Fife C, Grant L, et al. Guidelines for the treatment of arterial insufficiency ulcers. Wound Repair Regen. 2006;14(6):693-710. doi:10.1111/j.1524-475X.2006.00177.x
32. Federman DG, Ladiiznski B, Dardik A, Kelly M, Shapshak D, Ueno CM, et al. Wound Healing Society 2014 update on guidelines for arterial ulcers. Wound Repair Regen. 2016;24(1):127–135. doi:10.1111/wrr.12395
33. World Health Organization. Cancer pain relief. WHO;1986.
34. Senecal S. Pain management of wound care. Nurs Clin North Am. 1999;34(4):847–860.
35. World Health Organization. Cancer pain relief, 2nd ed, with a guide to opioid availability. WHO;1996.
36. Briggs M, Torra i Bou JE. Pain at wound dressing changes: a guide to management. In: European Wound Management Association Position Document. Pain at wound dressing changes. Medical Education Partnership LTD; 2002, pp.12–17.
37. Evidence-Based Medicine Working Group. Evidence-based medicine. A new approach to teaching the practice of medicine. JAMA. 1992;268(17):2420–2425. doi: 10.1001/jama.1992.03490170092032
38. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312(7023):71–72. doi: 10.1136/bmj.312.7023.71
39. Goldschneider KR, Good J, Harrop E, Liossi C, Lynch-Jordan A, Martinez AE, et al. Dystrophic Epidermolysis Bullosa Research Association International (DEBRA International). Pain care for patients with epidermolysis bullosa: best care practice guidelines. BMC Med. 2014;12:178. doi: 10.1186/s12916-014-0178-2
40. Slater D, Kunnathil S, McBride J, Koppala R. Pharmacology of nonsteroidal antiinflammatory drugs and opioids. Semin Intervent Radiol. 2010;27(4):400–411. doi: 10.1055/s-0030-1267855
41. Díaz-González F, Sánchez-Madrid F. NSAIDs: learning new tricks from old drugs. Eur J Immunol. 2015;45(3):679–686. doi: 10.1002/eji.201445222
42. Adelizzi RA. Clinical implications of NSAID pharmacokinetics: special populations, special considerations. J Am Osteopath Assoc. 1994;94(5):396–398, 401–403.
43. Mazario J, Gaitan G, Herrero JF. Cyclooxygenase-1 vs. cyclooxygenase-2 inhibitors in the induction of antinociception in rodent withdrawal reflexes. Neuropharmacol. 2001;40(7):937–946. doi: 10.1016/s0028-3908(01)00020-x
44. Stainton SM, Monogue ML, Baummer-Carr A, Shepard AK, Nugent JF, Kuti JL, et al. Comparative assessment of tedizolid pharmacokinetics and tissue penetration between diabetic patients with wound infections and healthy volunteers via in vivo microdialysis. Antimicrob Agents Chemother. 2017;62(1):e01880–17. doi: 10.1128/AAC.01880-17
45. Cabrera Maqueda JM, Fuentes Rumí L, Valero López G, Baidez Guerrero AE, García Molina E, Díaz Pérez J, et al. Antibiotic diffusion to central nervous system [Spanish]. Rev Esp Quimoter. 2018;31(1):1–12.
46. Denetclaw TH, Suehiro I, Wang PK, Tolliver GL. Successful treatment of ventriculostomy-associated meningitis caused by multidrug resistant coagulase-negative Staphylococcus epidermidis using low-volume intrathecal daptomycin and loading strategy. Ann Pharmacother. 2014;48(10):1376–1379. doi: 10.1177/1060028014542634
47. Clements TW, Tolonen M, Ball CG, Kirkpatrick AW. Secondary peritonitis and intra-abdominal sepsis: An increasingly global disease in search of better systemic therapies. Scand J Surg. 2021;110(2):139–149. doi: 10.1177/1457496920984078
48. Karimov SI, Babadzhanov BD, Teshaev OR, Beketov GI, Kasymov UK, Ruzmetov PIu. Role of prolonged intraarterial catheter therapy in general peritonitis [in Russian]. Khirurgiia (Mosk). 2000;(12):17–19.
49. Ouyang H, Ma W, Si T, Liu D, Chen P, Gerdtsson AS, et al. Systemic chemotherapy with or without hepatic arterial infusion chemotherapy for liver metastases from pancreatic cancer: a propensity score matching analysis. Clin Colorectal Cancer. 2023;22(1):111–119. doi: 10.1016/j.clcc.2022.10.007
50. Antsypovich EA, Molchanov VF, Kadyshev IuG, Brusnitsyna MA. Selective intraarterial application of Thienam and Vasoprostan in the treatment of purulent foot diseases in patients with diabetes mellitus [in Russian]. Klin Khir. 1998;(8):53.
51. Farhan N, Hassan Z, Ali MAM, Alqalaf Z, Rasul RE, Jeffery S. How can technology improve burn wound care: A review of wound imaging technologies and their application in burns-UK experience. Diagnostics (Basel). 2025;15(17):2277. doi: 10.3390/diagnostics15172277
52. Mendonça AC, Júnior JAF, Frade MAC, Barbosa RI, das Neves LMS, de Jesus Guirro RR, et al. Thermographic characterization of cutaneous ulcers of different etiologies. J Med Syst. 2020;44(9):160. doi: 0.1007/s10916-020-01612-8