Volume 40 Number 2

Introduction

Pain associated with chronic leg ulcers can be significant and impact wound healing and health-related quality of life. Although oral pain relief strategies are available, these are sometimes ineffective. Pain that lasts or recurs for more than 3 months is considered chronic and may result in the high consumption of oral opiates and other pain relievers, which can lead to misuse and the development of adverse effects, highlighting the need for alternative pain management strategies. Topical pain relief medications may be a promising alternative for the management of chronic painful leg ulcers. 

Two previous reviews^1,2 have reported on the use of topical agents and dressings for the management of pain associated with debridement of chronic leg ulcers. Their findings suggest that topical lidocaine/prilocaine cream may be useful for reducing acute pain in the context of leg ulcer debridement and that ibuprofen is effective in reducing chronic leg ulcer pain. As suggested by Briggs et al,¹ there is a considerable lack of data regarding the effect of topical pain relief agents on leg ulcer healing and long-term use, causing them to recommend further research in this area.

Since Briggs et al’s 2012 review,¹ the body of evidence for the use of topical analgesia and anesthetics for the management of wound-related pain associated with chronic leg ulcers has continued to grow. The purpose of this review is to assess whether topical anesthetic or local analgesic agents confer any benefit for these patients.

Methods

A systematic approach informed by Pare and Kitsiou³ was used for this review to ensure relevant literature was identified. The clinical problems that guided the literature review are as follows: (1) chronic leg ulcers are painful; (2) oral pharmacologic strategies for the treatment of wound-related pain associated with chronic leg ulcers are not always effective; and (3) topical agents and dressings may be useful in managing pain associated with chronic leg ulcers. These clinical problems led to the following question: In patients with chronic leg ulcers, is the application of topical local anesthetics or analgesics effective in reducing pain?

Search Strategy

An extensive literature review was conducted using the following electronic databases: Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Joanna Briggs Institute, PubMed, and the Cochrane Library. To ensure that relevant literature had not been missed during the electronic search, authors hand-searched international consensus documents and position statements related to wound management and their reference lists. 

The dates of the search ranged from January 1990 to August 2019. This time period was designed to predate the induction of lidocaine/prilocaine cream into the Australian Register of Therapeutic Goods in August 1991⁴ and its approval by the US FDA in 1992.⁵ Further, the use of topical opioids were first reported in the early 1990s.⁶ 

Search terms and combinations were as follows:

1. exp Foot Ulcer/ or Leg Ulcer/ or Varicose Ulcer/ 

2. (venous ulcer$ or varicose ulcer$ or arterial ulcer$ or mixed ulcer$ or leg ulcer$ or foot ulcer$ or stasis ulcer$ or (feet adj ulcer$)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]

3. 1 or 2

4. exp Anesthetics, Local/

5. Lidocaine/

6. Prilocaine/

7. topical local an?esthetics$.mp.

8. lidocaine.mp.

9. prilocaine.mp.

10. EMLA.mp.

11. eutectic mixture local an?esthetic$.mp.

12. 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11

13. Analgesics, Opioid/

14. exp Analgesics/

15. Administration, Topical/

16. 14 and 15

17. Anti-Inflammatory Agents, Non-Steroidal/

18. morphine.mp.

19. amitriptyline.mp.

20. capsaicin.mp.

21. ketamine.mp.

22. NSAIDs.mp.

23. non-steroidal anti-inflammator$.mp.

24. topical anti-inflammator$.mp.

25. 13 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24

26. 12 or 25

27. exp Pain/

28. pain$.mp.

29. 27 or 28

30. 3 and 26 and 29

31. limit 30 to yr=”2018 - Current”

Eligibility and Quality Assessment

Titles, abstracts, and articles were screened against the following inclusion criteria: 

〈 studies investigating topical local anesthetics lidocaine or prilocaine and topical analgesic agents such as ketamine, nonsteroidal anti-inflammatory drugs, opioids, tricyclic antidepressants (amitriptyline), or capsaicin on participants with chronic leg ulcers

〈 wound-related pain associated with chronic leg ulcers as a primary or secondary outcome

〈 studies where the topical local anesthetic or topical analgesic agent was the intervention or the control

〈 studies where at least one-third of participants had chronic leg ulcers

〈 human, adult, peer-reviewed studies published in the English language 

Case series and case reports were excluded. In addition, even though tetracaine 0.5%/adrenaline 0.05%/cocaine 11.8% and lidocaine/epinephrine 0.1%/tetracaine 0.1% also provide anesthesia to nonintact skin, the evidence reports concerns regarding their toxicity and expense,⁷ and therefore studies evaluating these products were not included.

Methodology assessment was guided by the CONSORT (Consolidated Standards of Reporting Trials) guidelines,⁸ Critical Appraisal Skills Programme checklists,⁹ and the wound component of the Cochrane Risk of Bias Tool.¹⁰

Results

The literature review identified a total of 406 articles. The number identified in each database was as follows: MEDLINE, 69; EMBASE, 91; CINAHL, 35; Joanna Briggs Institute, 7; Cochrane, 6; and PubMed, 198. Sixteen additional articles were identified through hand searching of international consensus documents and position statements. The full texts of five studies^11-15 could not be obtained despite repeated attempts and were therefore not included.

A total of 23 articles met the inclusion criteria and were included in the full-text review (Figure 1). These studies were classified into two major categories: topical analgesics (Table 1) and topical local anesthetics (Table 2). There were 19 randomised controlled trials (RCTs), one quasi-experimental study, two crossover studies, and one retrospective, observational medical record review (Figure 2). One of the included articles¹⁶ reported a subanalysis from a previous study. Topical analgesics were evaluated in 10 articles: ibuprofen foam was the intervention in seven articles, and morphine gel was evaluated in three articles. Local anesthetics were the interventions used in 13 studies. 

Figure 1. Prisma flow diagram of search outcomes

Table 1. Characteristics of included articles related to topical analgesic agents

Table 1 continued. Characteristics of included articles related to topical analgesic agents

Abbreviations: CLUs, chronic leg ulcers; NBS, numerical box scale; NR, not reported; NRS, numerical rating scale; QOL, quality of life; RCT, randomised controlled trial; s/c, subcutaneous; VAS, visual analog scale; VRS, verbal rating scale. 

^aArapoglou et al²² is a secondary analysis of a previous study by Domenech et al.¹⁹  

Table 2. Classification of included studies related to topical local anesthetic agents

Table 2 continued. Classification of included studies related to topical local anesthetic agents

Table 2 continued. Classification of included studies related to topical local anesthetic agents

Abbreviations: CLUs, chronic leg ulcers; LMX-4, liposomal lidocaine cream N₂O/O₂, Nitrous oxide/oxygen mixture; NR, not reported; NRS numerical rating scale; QOL, quality of life; RCT, randomised controlled trial; VAS, visual analog scale; VRS, verbal rating scale.

Figure 2. Classification of included studies

The majority of studies (n = 20) were conducted in Europe, most commonly in Sweden (n = 5). Outcome measurement time points ranged from 10 minutes to 12 weeks. Current research relating to topical local anesthetic or analgesic agents for painful chronic leg ulcers was limited; the majority of the literature was more than 5 years old (83%).

Category 1: Topical Analgesic Agents

For all studies investigating topical analgesic agents, pain was the primary outcome reported and a variety of pain assessment tools were used to assess pain, including the numeric rating scale, visual analog scale, visual rating sale, and numerical box scale. Venous leg ulcers were the predominant ulcer type, and the surface areas of leg ulcers were less than 54 cm². Wound size was reflected in the inclusion criteria in all of the studies except one.¹⁷

In six of the seven studies investigating ibuprofen foam, there was a statistically significant reduction in wound-related pain when compared with a placebo or standard care; the remaining study showed a reduction in wound-related pain compared with standard care. The dose of ibuprofen was the same in all studies (0.5 mg/cm² = 112.5 mg), although the dose was not reported in one study.¹⁶ Half of the studies compared ibuprofen foam with a placebo, and the other half with standard care. Although half of the studies in this review had large sample sizes (range, 120-835), some had fewer than 25 participants.^17,18 These small studies were not sufficiently powered to show a difference, likely contributing to type II error. Only four of the studies investigating ibuprofen reported an a priori sample size calculation.^16,19-21 

In general, the reporting of methodologies was poor in that important elements, such as method of randomization, allocation concealment, loss to follow-up, intention-to-treat analysis, blinding, and baseline comparability were not included. Gottrup et al²¹ was the only group that reported methodology appropriately against recommended criteria,^8-10 so their study’s level of bias could be determined more accurately.

Five of the seven studies in the ibuprofen group reported adverse events^16,17,19-21 related specifically to the intervention agent. These included local reactions such as infection, eczema, blisters, increased pain and wound size, erythema, bleeding, and periulcer deterioration. In one study, no adverse events relating to ibuprofen foam were reported during the study period,¹⁸ and the final study²² did not report on adverse effects at all.

It is unclear whether topical morphine gel was effective in reducing pain associated with venous, arterial, or mixed leg ulcers because of the small sample sizes in the three related studies. Morphine gel (morphine sulfate injection mixed with a hydrogel) is usually applied daily to painful chronic or palliative wounds for pain relief,^23,24 although twice-daily application is often required.²⁵ All studies investigating morphine gel used a placebo gel as the comparator.^25-27 A range of doses were reported, including 0.5 mg/cm², 10 mg, and 0.5%/g. All of these studies had fewer than 25 participants (Table 1), so type II error was likely. None reported undertaking a sample size calculation a priori, and the reporting of methodologies was poor.

All three studies investigating morphine gel reported adverse events associated with the intervention.^25-27 Local adverse reactions included itching, burning pain, stinging, eczema, ineffective pain relief, and infection. Systemic adverse reactions included dizziness, nausea, vomiting, and drowsiness.

Category 2: Topical Local Anesthetic Agents

Twelve studies investigated lidocaine/prilocaine cream (EMLA 5%) in the context of debridement of chronic leg ulcers (Table 2), and one study²⁸ investigated lidocaine/prilocaine cream for chronic pain associated with chronic leg ulcers. Pain was the primary outcome in all but two studies,^29,30 and the visual analog scale was the predominant pain assessment tool used. The findings in this group suggest that lidocaine/prilocaine cream was effective in reducing wound-related pain associated with debridement of chronic leg ulcers in all but two studies,^31,32 although the reporting of methodologies in all but one study²⁸ was poor. 

Venous leg ulcers were again the predominant leg ulcer type in studies included in this group. The surface area of each chronic leg ulcer was less than 50 cm² (86%) in most of the studies. 

Nine studies compared lidocaine/prilocaine cream 5% with either a topical placebo,^29,33-35 lidocaine 10% spray,³¹ lidocaine/prilocaine cream 2%,³² or nitrous oxide-oxygen mixture inhalation;^36,37 the comparator in one study was unknown.³⁸ One RCT compared lidocaine/prilocaine cream to usual wound care.²⁸ One retrospective, observational study³⁹ evaluated the effectiveness of lidocaine/prilocaine cream 5% in a sample of 1,084 participants with a variety of wound types, including chronic leg ulcers. The number of total applications of the cream ranged from 1 to 28, and most studies applied it 30 minutes prior to debridement. Two studies extended the application time to 45 minutes,^29,35 and two studies to 60 minutes.^39,40 One study applied lidocaine/prilocaine cream for only 10 minutes,³¹ and another repeated daily 24-hour doses for 4 weeks.²⁸ The maximum dose was 10 g in 69% of the studies.^{28,30,32-35,37,40} However, in the medical record review conducted by Blanke and Hallern,³⁹ some participants received up to 150 g of lidocaine/prilocaine cream topically. 

Findings from three studies measuring plasma concentrations of lidocaine and prilocaine in the 5% and 2% creams indicated that toxic levels are not reached after repeated applications for debridement.^30,32,33 In Enander et al,³² plasma concentrations were higher for individuals with arterial leg ulcers compared with venous leg ulcers. However, this finding is not supported by a more recent study by Effendy et al,³⁰ which indicated that ulcer type does not have any impact on plasma concentrations, although leg ulcer size did have a significant impact.

More than half of the studies reported minor adverse reactions, which were largely local skin reactions such as burning, pallor, erythema, itching, stinging, and edema.^{28,29,32-34,37-39} No major adverse reactions to lidocaine/prilocaine cream were reported.

In the majority of studies, the sample sizes were small (range, 10-110), and there were fewer than 70 participants in 9 of 13 studies in this group. Only two studies reported undertaking a sample size calculation a priori.^35,37 However, a statistically significant reduction in pain during debridement was observed in all but two of the studies investigating debridement,^31,32 and a statistically significant reduction in chronic wound-related pain during and after dressing change was observed in one study.²⁸

Assessment of Methodological Quality

Nineteen of the 23 studies included in this review were RCTs. The methodological quality of the RCTs related to topical analgesic and anesthetic agents is presented in Tables 3 and 4, respectively.

Two studies, one in the topical analgesic group¹⁷ and one in the topical local anesthetic group,³⁶ were crossover studies. One study in the topical local anesthetic group³⁰ was a quasi-experimental study, and this was the only one that reported baseline comparability.³⁰ One study used a crossover design to compare ibuprofen foam with placebo foam as a primary dressing for painful chronic leg ulcers;¹⁷ another compared lidocaine/prilocaine cream and nitrous oxide-oxygen mixture inhalation³⁶ as treatments for chronic leg ulcers before debridement. Two RCTs^32,33 included data from small preliminary observational studies. One investigated the application times of lidocaine/prilocaine cream,³³ and the other, plasma concentrations.³²

Table 3. Assessment of methodological quality of randomised controlled trials: topical analgesic agents

Abbreviations: CLU, chronic leg ulcer; ITT, intent to treat; NR, not reported; RCT, randomised controlled trial.

Discussion

These findings suggest that ibuprofen foam may be successful in reducing chronic leg ulcer pain; however, there were insufficient data to suggest similar effectiveness for the application of morphine gel. Lidocaine/prilocaine cream was the local anesthetic agent used in all studies in the topical anesthetic group and was applied to chronic leg ulcers to prevent acute pain associated with debridement in all but one. These findings suggested that lidocaine/prilocaine cream was effective when used for this purpose. One study suggests that lidocaine/prilocaine cream may also be effective in reducing chronic pain associated with chronic leg ulcers when used daily as a primary dressing.

The majority of the studies in this review did not conform to CONSORT reporting requirements,⁸ and therefore the risk of selection, detection, and performance biases often could not be determined. The insufficient information provided in most of the articles leads to the assumption of poor trial quality, but this cannot truly be assessed.⁴¹ Nevertheless, only 43% of the RCTs blinded the participants and investigators, 12% reported how their allocation sequence was generated, and only 30% reported allocation concealment. The risk of attrition bias was also high, with fewer than 30% of RCTs reporting whether participants were accommodated in an intention-to-treat analysis, and fewer than 15% reporting participant withdrawals. One study in this group had a dropout rate of 29%. Further, most studies included in this review were older than 5 years, although it is recognised that only valuing recent evidence over robust evidence may misinform practice.⁴²

To improve the validity of a clinical trial, an appropriate sample size is important. A small sample size increases the potential for type II error, resulting in the decreased applicability and utility of findings in the clinical setting.⁴³ Conversely, clinical trials with larger sample sizes can result in wasted resources, decreasing the validity or accuracy because of low response rates and difficulty maintaining data quality.⁴³ In this review, 14 of the 23 studies had a sample size of fewer than 100. All 3 studies investigating morphine gel had sample sizes of fewer than 25, as did 2 of the 7 investigating ibuprofen foam, and 9 of the 13 investigating lidocaine/prilocaine cream. Even though the retrospective, observational medical record review³⁹ included in this analysis had a very large sample size, the study design has other inherent methodological limitations that sample size alone could not overcome.

In this review, the findings related to topical analgesic and topical local anesthetic agents for the relief of chronic leg ulcer pain indicate that topical agents (except for morphine gel) are effective. What this review has added to the body of knowledge is that, to date, the only topical formulations used as primary dressings for chronic leg ulcer pain have been ibuprofen foam and morphine gel, and rarely, lidocaine/prilocaine cream. For decades, lidocaine/prilocaine cream has been the predominant and most long-standing topical pain reliever for relief of operative pain associated with the debridement of chronic leg ulcers. Only recently has it been investigated as a primary dressing to relieve chronic wound-related pain.

Table 4. Assessment of methodological quality of randomised controlled trials: topical local anesthetic agents

Abbreviations: CLU, chronic leg ulcer; NR, not reported; MMS, Mini-Mental Score; RCT, randomised controlled trial; VAS, visual analog scale; VRS, verbal rating scale.

Limitations

Language bias was a limitation of this review, and publication bias was unclear. Further, interviews with trial investigators may have assisted in assessing study quality more accurately;⁴¹ this was not carried out.

Literature Gaps

Topical analgesics and anesthetics provide an important pain relief alternative when oral analgesia is ineffective or results in significant adverse effects. There are a limited number of studies that examine the use of these agents to manage chronic leg ulcer pain. Available studies are limited mostly by small sample sizes and poor methodological quality. Accurate assessment of methodological quality was disadvantaged by the poor reporting outlined in the available literature.

The strongest evidence available supports intermittent, short applications of lidocaine/prilocaine cream prior to debridement for operative pain relief, which has been shown to be systemically safe without negatively impacting wound healing. The evidence for the effectiveness of lidocaine/prilocaine cream in debridement, together with one pilot RCT using it as a primary dressing, suggest that it may be effective in managing chronic pain for individuals with chronic leg ulcers. This strategy would lead to reduced wound-related pain for longer periods, which in turn may have a positive impact on wound healing and health-related quality of life.

Conclusions

This review has identified limited, inconsistent evidence for the use of topical analgesics and topical local anesthetic agents to treat painful chronic leg ulcers. Although there is the need for further research regarding the use of topical agents to relieve chronic wound-related pain, lidocaine/prilocaine cream and ibuprofen foam appear to be effective agents for reducing wound-related pain associated with chronic leg ulcers. The effective use of topical agents could reduce the need for systemic pain relief agents, mitigating potential adverse effects.

Practice pearls

• Pain associated with chronic leg ulcers can be significant and impact wound healing and health-related quality of life. 
• Topical lidocaine/prilocaine 5% cream is effective for relieving pain during the debridement of chronic leg ulcers. 
• Topical lidocaine/prilocaine 5% cream and ibuprofen foam may be promising alternatives to oral pain medications to treat chronic wound-related pain.
• Evidence for the use of topical analgesics and local anesthetic agents to treat painful chronic leg ulcers is inconsistent. Further research is needed.

Conflict of Interest

The authors declare no conflicts of interest.

Funding

The authors received no funding for this study.

Author(s)

Anne Purcell*
PhD, NP, RN,
Nurse Practitioner Wound Management, Central Coast Local Health District Community Nursing Service, Wyong, New South Wales, Australia
Email  anne.purcell@health.nsw.gov.au

Thomas Buckley
PhD, RN,
Associate Professor, Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

Jennie King
PhD, RN,
Nursing & Midwifery Research Consultant, Nursing & Midwifery Directorate, Central Coast Local Health District, Gosford, New South Wales, Australia, Clinical Senior Lecturer, Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

Wendy Moyle
PhD, RN,
Professor, Program Director, Healthcare Practice and Survivorship, Menzies Health Institute, Southport, Queensland, Australia 

Andrea P. Marshall
PhD, RN,
Professor of Acute and Complex Care Nursing, Gold Coast Hospital and Health Service Nursing and Midwifery Education and Research Unit, Southport, Queensland, Australia

* Corresponding author

References

1. Briggs M, Nelson EA, Martyn-St James M. Topical agents or dressings for pain in venous leg ulcers. Cochrane Database Syst Rev 2012(11):CD001177.
2. Vanscheidt W, Sadjadi Z, Lillieborg S. EMLA anesthetic cream for sharp leg ulcer debridement: a review of the clinical evidence for analgesia efficacy and tolerability. Eur J Emerg Med 2001;11:90-6.
3. Pare G, Kitsiou S. Methods for literature reviews. In: Lau F, Kuziemsky C, eds. Handbook of eHealth Evaluation: An Evidence-Based Approach. Victoria, BC, Canada: University of Victoria; 2017:157-80. 
4. Australian Department of Health Therapeutic Goods Administration. Public Summary. 2018. www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=FD3D09E3800470D2CA 25821F003C9C0C&agid=(PrintDetailsPublic). Last accessed February 19, 2020.
5. Food and Drug Administration. Approved Drug Products with Therapeutic Equivalence Evaluations. 40th ed. 2020. www.fda.gov/media/71474/download. Last accessed February 19, 2020.
6. Weinberg L, Peake B, Tan C, Nikfarjam M. Pharmacokinetics and pharmacodynamics of lignocaine: a review. World J Anesthesiol 2015;4(2):17-29.
7. Kumar M, Chawla R, Goyal M. Topical anesthesia. J Anaesthesiol Clin Pharmacol 2015;31(4):450-6.
8. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Br Med J 2010;340:c332.
9. Critical Appraisal Skills Programme. CASP Checklists. 2018. https://casp-uk.net/casp-tools-checklists. Last accessed February 4, 2020.
10. Cochrane Wounds. Table 8.5.d: criteria for judging risk of bias in the ‘risk of bias’ assessment tool. 2011. https://handbook-5-1.cochrane.org/chapter_8/table_8_5_d_criteria_for_judging_risk_of_bias_in_the_risk_of.htm. Last accessed February 4, 2020.
11. Johns BA. EMLA cream for the debridement of venous leg ulcers. J Fam Pract 1999;48(5):332.
12. Johnson C, Repper J. A double blind placebo controlled study of lidocaine/prilocaine cream (EMLA 5%) used as a topical analgesic for cleansing and redressing of leg ulcers. Astra Pain Control AB (Confidential Report); 1992.
13. Larsson-Stymne B, Rostein A, Widman M. An open clinical study on plasma concentrations of lidocaine and prilocaine after application of EMLA 5% cream to leg ulcers. Clin Dermatol 2000;1990(22-25 May).
14. Slawson D. How effective is an eutectic mixture of local anesthetics (EMLA) cream in reducing the pain of repeated mechanical debridement of venous leg ulcers? Evid Based Pract 1999;2(5).
15. Wanger L, Eriksson G, Karlsson A. Analgesic effect and local reactions of repeated application of EMLA lidocaine prilocaine cream for the cleansing of leg ulcers. Paper presented at the Clinical Dermatology in the Year 2000; London, England. 
16. Romanelli M, Dini V, Polignano R, Bonadeo P, Maggio G. Ibuprofen slow-release foam dressing reduces wound pain in painful exuding wounds: preliminary findings from an international real-life study. J Dermatological Treat 2009;20(1):19-26.
17. Jorgensen B, Friis GJ, Gottrup F. Pain and quality of life for patients with venous leg ulcers: proof of concept of the efficacy of Biatain-Ibu, a new pain reducing wound dressing. Wound Repair Regen 2006;14(3):233-9.
18. Sibbald RG, Coutts P, Fierheller M, Woo K. A pilot (real-life) randomized clinical evaluation of a pain-relieving foam dressing: (ibuprofen-foam versus local best practice). Int Wound J 2007;4 Suppl 1:16-23.
19. Domenech RPi, Romanelli M, Tsiftsis DD, et al. Effect of an ibuprofen-releasing foam dressing on wound pain: a real-life RCT. J Wound Care 2008;17(8):342-8.
20. Fogh K, Andersen MB, Bischoff-Mikkelsen M, et al. Clinically relevant pain relief with an ibuprofen-releasing foam dressing: results from a randomized, controlled, double-blind clinical trial in exuding, painful venous leg ulcers. Wound Repair Regen 2012;20(6):815-21.
21. Gottrup F, Jorgensen B, Karlsmark T, et al. Reducing wound pain in venous leg ulcers with Biatain Ibu: a randomized, controlled double-blind clinical investigation on the performance and safety. Wound Repair Regen 2008;16(5):615-25.
22. Arapoglou V, Katsenis K, Syrigos KN, et al. Analgesic efficacy of an ibuprofen-releasing foam dressing compared with local best practice for painful exuding wounds. J Wound Care 2011;20(7):319-20, 322-5.
23. Northamptonshire Healthcare. MMG029 Guidelines for the Use of Topical Morphine for Painful Skin Ulcers in Specialist Palliative Care. November 2019. www.nhft.nhs.uk/download.cfm?doc=docm93jijm4n1573. Last accessed February 19, 2020.
24. Shanmugam VK, Couch KS, McNish S, Amdur RL. Relationship between opioid treatment and rate of healing in chronic wounds. Wound Repair Regen 2017;25(1):120-30.
25. Jansen MM, van der Horst JC, van der Valk PG, Kuks PF, Zylicz Z, van Sorge AA. Pain-relieving properties of topically applied morphine on arterial leg ulcers: a pilot study. J Wound Care 2009;18(7):306-11.
26. Bastami S, Frodin T, Ahlner J, Uppugunduri S. Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study. Int Wound J 2012;9(4):419-27.
27. Vernassiere C, Cornet C, Trechot P, et al. Study to determine the efficacy of topical morphine on painful chronic skin ulcers. J Wound Care 2005;14(6):289-93.
28. Purcell A, Buckley T, Fethney J, King J, Moyle W, Marshall AP. The effectiveness of EMLA as a primary dressing on painful chronic leg ulcers—a pilot randomized controlled trial. Adv Skin Wound Care 2017;30(8):354-63.
29. Lok C, Paul C, Amblard P, et al. EMLA cream as a topical anesthetic for the repeated mechanical debridement of venous leg ulcers: a double-blind, placebo-controlled study. J Am Acad Dermatol 1999;40(2 Pt 1):208-13.
30. Effendy I, Gelber A, Lehmann P, Huledal G, Lillieborg S. Plasma concentrations and analgesic efficacy of lidocaine and prilocaine in leg ulcer-related pain during daily application of lidocaine-prilocaine cream (EMLA) for 10 days. Br J Dermatol 2015;173(1):259-61.
31. Cuomo R, D’Aniello C, Grimaldi L, et al. EMLA and lidocaine spray: a comparison for surgical debridement in venous leg ulcers. Adv Wound Care 2015;4(6):358-61.
32. Enander M, Nilsen T, Lillieborg S. Plasma concentrations and analgesic effect of EMLA (lidocaine/prilocaine) cream for the cleansing of leg ulcers. Acta Derm Venereol 1990;70(3):227-30.
33. Holm J, Andren B, Gafford K. Pain control in the surgical debridement of leg ulcers by the use of a topical lidocaine-prilocaine cream, EMLA. Acta Derm Venereol 1990;70(2):132-6.
34. Rosenthal D, Murphy S, Gottschalk R, Baxter M, Lycka B, Nevin K. Using a topical anesthetic cream to reduce pain during sharp debridement of chronic leg ulcers. J Wound Care 2001;10(1):503-5.
35. Agrifoglio G, Domanin M, Baggio E, et al. EMLA anesthetic cream for sharp debridement of venous leg ulcers: a double masked placebo controlled study. Phlebology 2000;15(2):81-3.
36. Traber J, Held U, Signer M, Huebner T, Arndt S, Neff TA. Analgesic efficacy of equimolar 50% nitrous oxide/oxygen gas premix (Kalinox^®) as compared with a 5% eutectic mixture of lidocaine/prilocaine (EMLA^®) in chronic leg ulcer debridement. Int Wound J 2017;14(4):606-15.
37. Claeys A, Gaudy-Marqueste C, Pauly V, et al. Management of pain associated with debridement of leg ulcers: a randomized, multicentre, pilot study comparing nitrous oxide-oxygen mixture inhalation and lidocaine-prilocaine cream. J Eur Acad Dermatol Venereol 2011;25(2):138-44.
38. Hansson C, Holm J, Lillieborg S, Syren A. Repeated treatment with lidocaine/prilocaine cream (EMLA) as a topical anesthetic for the cleansing of venous leg ulcers. A controlled study. Acta Derm Venereol 1993;73(3):231-3.
39. Blanke W, Hallern B. Sharp wound debridement in local anaesthesia using EMLA cream: 6 years’ experience in 1084 patients. Eur J Emerg Med 2003;10(3):229-31.
40. Holst RG, Kristofferson A. Lidocaine-prilocaine cream (EMLA cream) as a topical anesthetic for the cleansing of leg ulcers. The effect of length of application time. Eur J Dermatol 1998;8(4):245-7.
41. Soares HP, Daniels S, Kumar A, et al. Bad reporting does not mean bad methods for randomized trials: observational study of randomized controlled trials performed by the Radiation Therapy Oncology Group. Br Med J 2004;328(7430):22-4.
42. Shorten A. When is the evidence too old? BMJ Blogs. 2013. https://blogs.bmj.com/ebn/2013/09/26/when-is-the-evidence-too-old. Last accessed February 4, 2019.
43. Kumar GS. Importance of sample size in clinical trials. Int J Clin Exp Physiol 2014;1(1):10-2.