EMLA anaesthetic cream for sharp leg ulcer debridement: a review of the clinical evidence for analgesic efficacy and tolerability

ARTICLE

The prevalence of chronic leg ulcers is related to the presence of arterial and venous disease, and hence to the age of the population. It is estimated that 1.5% of elderly people will develop a leg ulcer [1], although one third of patients experience their first ulcer before the age of 50 [2]. With a steadily increasing elderly population, the number of patients with leg ulcers of vascular origin is likely to increase over the next few years. Seventy to ninety per cent of the ulcers are caused by venous insufficiency, the annual treatment costs of which have been estimated at £2-3,000 per patient in the UK [1].

Need for treatment of pain in leg ulcer patients

Having a leg ulcer has deleterious effects on the patient's quality of life, causing emotional reactions, decreased mobility, disturbed sleep and social isolation [3-5]. A large proportion of patients report discomfort from physical symptoms such as itching, swelling and discharge and, above all, pain. In one study of non-diabetic ulcer patients as many as 65% reported severe pain [4]. Pain was previously considered to be a symptom of patients with arterial ulcers, although later research has shown that 65-80% of venous patients do report severe pain from their ulcers [6]. Pain is in general inadequately controlled in these patients. Interviews with another group of venous leg ulcer patients revealed that the overwhelming experience of leg ulceration was of it being painful [7]. Three of the above studies focused on the chronic pain component; however, Noonan and Burge [5] also questioned patients about their experience of dressing changes: 36% of venous ulcer patients had felt pain when their dressings were changed, usually because the dressing stuck to the ulcer. In addition, it is known that 67% of venous leg ulcer patients undergoing sharp debridement without anaesthesia experience post-debridement pain for at least four hours after the hospital visit [8].

To improve the quality of life of patients with a leg ulcer, it seems well justified that every effort should be made to provide analgesia for both chronic and treatment-related pain.

The importance of active local ulcer care

Systemic treatment of underlying diseases and the use of compression therapy are essential for the healing of venous leg ulcers. In addition, for all types of ulcer, active local ulcer care is important in order to accelerate healing. The removal of necrotic and devitalised tissue, slough and fibrin from the ulcer reduces the risk of infections, reduces odour and promotes the growth of granulation tissue. This is generally recognised to improve healing [9-11]. Debridement also improves the results of skin grafting [12]. Grafting can be utilised for all ulcers, but may be particularly indicated in large venous ulcers [12]. Pinch grafting is a simple method, which can easily be employed even in primary healthcare [13]. It also reduces the severity of chronic ulcer pain, often as early as within 24 hrs of the procedure [13].

Various types of technique such as mechanical, enzymatic, surgical and sharp debridement can bring about a clean ulcer.

Sharp debridement techniques

Surgical debridement and sharp debridement are the fastest methods of achieving a clean ulcer [11]. The use of hydrocolloids between debridements speeds up the cleansing process [14]. Surgical debridement is performed with a scalpel in the operating theatre. Bleeding usually occurs, resulting in activation of platelets and the release of cytokines and growth factors, which positively influence the healing environment [15, 16]. While this is a fast and effective means of achieving a clean ulcer, it is usually expensive and painful and holds inherent risks such as bleeding, infection, injury to vital tissues and anaesthetic complications. Patients with thrombocytopenia and coagulation disorders require particular attention. Topical anaesthesia is generally insufficient for this surgical technique, which may involve excision of infected soft tissue down to the level of the bone.

Sharp debridement is less aggressive than surgical debridement, but has the advantage of rapidly improving the healing conditions in the ulcer [17]. It may involve the use of a scalpel, a sharp curette, scissors and forceps. Devitalised tissue and fibrinous plaques are removed with the aim of promoting the growth of healthy, red granulation tissue [18]. Sharp debridement does not require an operating theatre and can be performed on out-patients. The potential risks include injury to healthy granulation tissue and underlying blood vessels, and proper training of personnel is therefore necessary [11]. The removal of necroses and fibrin layers should be as radical as required, while being as lenient as possible, and should be undertaken at least twice a week [19]. Adequate pain control is essential to ensure that thorough cleansing of the ulcer is completed satisfactorily and not interrupted prematurely.

The positive effect of sharp debridement on healing was evaluated in a study of diabetic foot ulcers [10]. In this multicentre study the effect of growth hormone treatment locally applied to the ulcer was compared with placebo. A lower rate of healing was observed in centres that performed less frequent debridement, both in the active treatment group and in the placebo group. In ulcers of vascular origin a placebo-controlled study of a topical anaesthetic found a significant correlation between the ulcer area at the end of the study and the number of sharp ulcer debridements performed [20].

Requirements for topical anaesthetics for ulcer debridement

A topical anaesthetic suitable for use in leg ulcer debridement should have a) documented clinical evidence of efficacy, b) low systemic toxicity, c) low potential for sensitisation, and d) no adverse effects on healing.

Some years ago, sterile solutions were used for the cleansing of leg ulcers. However, it was recognised that all chronic leg ulcers are colonised by bacteria, even when clinical signs of infection are absent. Consequently, in many European countries, ordinary tap water is currently used [21-23]. There is no need, therefore, for the sterility of topical anaesthetics used in chronic leg ulcers.

Topical anaesthetics studied for ulcer debridement

A Medline search on leg ulcers, anaesthetics/analgesics and topical administration conducted over the time period 1966 to June 2000 revealed controlled studies of one product only: the lidocaine/prilocaine cream, EMLA^® (AstraZeneca). This review includes all EMLA studies on leg ulcers published by the time of the Medline search. In addition, abstracts and two studies accepted for publication were identified from the reference lists in the retrieved articles.

EMLA contains a eutectic mixture of the two local anaesthetics lidocaine and prilocaine (25 mg of either agent per gram of cream), a thickener (Carbopol^®) and an emulsifier (Arlatone^®). EMLA does not contain any preservatives. The oil-in-water emulsion of the eutectic mixture facilitates the percutaneous absorption through intact skin. A 1-2 hr application under occlusion induces cutaneous analgesia of at least 3-4 hrs duration after removal of the cream [24]. On the other hand, anaesthesia of the genital mucosa is achieved after only five minutes EMLA treatment [25]. The minimum effective application time on leg ulcers, therefore, deserves special attention. We shall now review the clinical evidence for the anaesthetic efficacy and tolerability of EMLA when used for leg ulcer debridement.

Studies of the efficacy of EMLA for sharp debridement

Altogether twelve studies of the analgesic efficacy of EMLA for sharp leg ulcer debridement, constituting all the published studies retrieved, are reviewed; two studies of the effect of the length of application time [23, 26], one dose-comparison study [27], three open uncontrolled studies [28-30] (Table I), four double-blind placebo-controlled studies [20, 26, 31, 32] and two open comparisons with a control group not receiving topical anaesthesia or vehicle. One of the two latter studies was randomised [8] (Table II), but the second one was not [33].

Study methods

All studies shared common experimental procedures with regard to EMLA cream. At the minimum stipulated time before ulcer debridement, varying from 10 to 60 min between studies, a thick layer of EMLA was applied to the ulcer (1-3 g/10 cm² of ulcer surface), with a maximum of 10 g per treatment session. The cream was covered with ordinary household plastic cling film, wrapped around the leg to form an occlusive dressing. The terminology used to describe the type of debridement performed was "cleansing" and "mechanical debridement"; however, all but one publication included in this review describe the use of a sharp curette, a bistoury, or tweezers and scissors - in other words, techniques which are nowadays often named "sharp debridement" [10, 11]. One study employed a CO₂ laser as a debriding tool [33].

Assessment of pain

The patients rated pain from the debridement procedure on a visual analogue scale (VAS) and/or a verbal rating scale (VRS). The VAS was generally a horizontal, ungraduated 100 mm line [34] where the left end-point of the line was marked "no pain" and the right end-point was marked "worst possible pain" or similar. The results are presented as the VAS score in millimetres or centimetres. In most studies that used the VRS scale, the patients rated their pain on a four-point verbal scale as: no pain, mild/slight, moderate, or severe pain. A VAS has been shown to provide more sensitive pain measurement than a VRS [34].

Studies of dose and length of cream application

In an open study Holm et al. [26] assessed the analgesic efficacy of 10, 20 or 30 min of EMLA treatment in a small number of patients. Thirty minutes treatment was chosen for a larger study of 41 patients; altogether 82% of patients reported no or only slight pain from debridement (Table I). The median VAS score was 13.5.

In an open randomised study Holst et al. compared three application times of EMLA: 10, 20 or 60 min [23]. Patients were stratified according to ulcer aetiology (arterial or venous) into the treatment groups. The use of analgesics was allowed during the study, and they were taken by 65% of patients. The same physician performed the sharp debridement in all patients. The patients' perception of pain from debridement decreased significantly with increasing duration of EMLA treatment (p = 0.001). Median VAS pain scores in the 10, 20 and 60 min groups were 41, 20 and 8, respectively. The authors concluded that a minimum of 20 min treatment gives substantial pain relief in the majority of patients. In patients scheduled for repeated debridements and experiencing pain after 20-30 min EMLA treatment, the application time may be increased to 60 min.

The local anaesthetic efficacy of EMLA 5% cream was compared with that of a 2% cream in a double-blind crossover study by Enander et al. [27]. While the two strengths of the cream had similar anaesthetic efficacy for debridement, post-cleansing pain tended to be more frequent with the 2% cream (8/10 patients compared to 4/9 patients, n.s.), suggesting a possible difference in duration of analgesia.

An open uncontrolled study by Barghorn et al. also suggested that 30 min treatment with EMLA may provide adequate pain relief for debridement (Table I). In another study without a control group, the analgesic efficacy was found to be consistent during repeated application of EMLA, in two to three sessions a week for up to two months [29].

In summary, the above studies suggest a possible analgesic effect of EMLA 5% cream, when applied under occlusion for a minimum of 20-30 min prior to sharp debridement.

Placebo-controlled studies of analgesic efficacy

Conclusive evidence of analgesic efficacy should be provided by randomised double-blind studies. Four double-blind placebo-controlled EMLA studies are available and, in addition, one open randomised study (Table II).

Holm et al. in Sweden [26] published the first placebo-controlled study of topical anaesthesia with EMLA cream for leg ulcer debridement. They included patients with ulcers of arterial and of venous origin. EMLA-treated patients rated debridement pain as a median of 18.5 on the VAS, while placebo-treated patients gave a median score of 84, a highly significant difference (Table II). This corresponded to a VRS rating of none or slight pain in 69% and 29% of EMLA- and placebo-treated patients, respectively. The median VAS scores in the EMLA and placebo groups in patients with venous ulcers were 17 and 89, and in patients with arterial ulcers 21.5 and 33.5, respectively. The arterial group included 6 patients with concomitant diabetes (4 were in the placebo group). Diabetics may have decreased pain sensitivity due to peripheral neuropathy. However, the results remained significant when the diabetics were excluded from the analysis.

These findings were confirmed in a Canadian study of patients with arterial, venous and mixed ulcer aetiology [31] (Table II), as well as in a French study of up to 15 repeated debridements in venous patients or patients with a slight arterial component [20] (Fig. 1). Lok et al. also found that the number of patients who prematurely interrupted at least one debridement because of pain was significantly higher (p < 0.001) in the placebo group (75.8%) than in the EMLA group (41.7%). In this study EMLA significantly reduced debridement pain in spite of the fact that premedication with analgesics was given to all patients one hour before debridement. Pain scores in placebo-treated patients, all of whom had received a combination of centrally and peripherally acting analgesics (Table II), averaged 50-60 on the VAS, corresponding to moderate or severe pain. These data clearly show that this type of oral analgesic alone is inadequate for the relief of procedure-related pain, such as debridement.

The effectiveness of EMLA in a population of venous ulcer patients was shown both in Italy using double-blind methodology [32] and in Sweden using an open randomised study design comparing EMLA with a control group receiving neither local anaesthesia nor vehicle [8] (Table II). In the latter study a significant difference in pain score between groups was observed although, prior to each debridement session, 18-45% of patients in both groups had used analgesics and/or nonsteroidal antiinflammatory agents (Dr. Hansson, personal communication). EMLA also reduced the frequency of post-debridement pain from 67% in the control group to 30% in the EMLA group. The superior post-procedure analgesia in the EMLA group lasted for at least 4 hrs after the procedure.

An additional study used a CO₂ laser for debridement of venous leg ulcers [33]. Fifteen patients were treated with EMLA for 30 min before debridement, and their pain scores were compared with an open non-randomised control group of seven patients who underwent debridement without topical anaesthesia. The mean VAS pain score was 12.8 in the EMLA group and 52 in the control group (p < 0.001). This was the only study where a laser was used for debridement.

The five randomised controlled studies provide convincing evidence that EMLA is effective in reducing sharp debridement pain, both in a Dermatology Department and in a Vascular Surgery Department setting. EMLA significantly reduced the pain even when patients were premedicated with analgesics. EMLA is effective in populations with ulcers of various vascular aetiology and in venous ulcer patients. In studies including patients with arterial disease, however, there were too few patients to demonstrate analgesic efficacy in this subgroup.

Studies of clinical outcomes

Can reduced debridement pain entail other clinical advantages? The following three controlled studies evaluated clinical outcomes such as the adequacy of the debridement procedure and the number of debridements necessary: Holm et al. [26] rated in each patient subjectively the quality of debridement as satisfactory or not. The judgement "satisfactory" was given in 88% of patients in the EMLA group compared to 43% in the placebo group (p = 0.01).

The ease of the debridement procedure in relation to standard therapy (without topical anaesthesia) was assessed by Agrifoglio et al. The investigators considered debridement to be easier in 59% of EMLA-treated patients versus 36% of placebo-treated patients [32].

Lok et al. evaluated as a primary objective the outcome "time to clean ulcer" in a placebo-controlled study of up to fifteen repeated debridements [20] (Table II). Patients were required to have debris and necrosis on 50% or more of the ulcer area at study entry. A clean ulcer was defined as having 75% of the ulcer free from necrotic and fibrinous tissue and crusts. Debridement was performed at least three times in the first week and then as often as judged necessary. If the ulcer was not clean after 15 debridements, the patient discontinued the study. At the end of the study 67% of patients in the EMLA group had a clean ulcer compared to 33% in the placebo group (p = 0.008, Fig. 2). The median number of debridements for a clean ulcer was 11.5 in the EMLA group, whereas it exceeded 15 in the placebo group (p = 0.019), i.e. fewer patients than required to reach the median had a clean ulcer in the placebo group. Extrapolation of the results suggested a saving of about 8 to 10 treatment sessions with the use of anaesthetic cream. These results imply a large potential for savings in healthcare cost. In addition, the ulcer area at the end of the study was found to be correlated significantly with the number of debridements [20]. In other words, the ulcer area decreased significantly with an increased number of debridements.

Studies of tolerability

The most common local reaction after EMLA treatment was a transient burning sensation reported by approximately 15% of patients [26]. Slight local redness and paleness was observed in the same study in 3% and 2% of patients, respectively. These reactions appear to be typical for all published studies of EMLA on leg ulcers. Holst et al. reported one case of moderate maceration of the skin edges [23]. In three studies the tolerability of repeated EMLA treatment was assessed (Table III). Local reactions did not increase in frequency or severity with increasing number of treatments. The bacterial flora of the EMLA-treated ulcers did not change with repeated treatments and did not differ from that of control patients [8, 29]. No adverse effects on ulcer area were reported. In summary, EMLA was well tolerated in leg ulcer patients.

No case of sensitisation occurred in the clinical studies (Table III). Lidocaine and prilocaine belong to the amide group of local anaesthetics, which is known to have a very low potential for sensitisation. In contrast, ester-type local anaesthetics such as benzocaine and tetracaine (amethocaine) are common sensitisers [35]. There is, however, a case report of a patient with a painful arterial ulcer who developed allergic contact dermatitis after twice daily treatments with EMLA for three months [36]. Similarly, following long-term daily use of EMLA for haemodialysis cannulation (7 months) [37] or painful postherpetic neuralgia (1 month) [38], contact allergy to the prilocaine component of the cream was diagnosed. In all three cases patch testing to lidocaine was negative. Although some cases may not have been published, this is an extremely low frequency of skin sensitisation considering the long and widespread use of EMLA.

A recent case report describes the occurrence of seizures in an 84-year-old woman after 17 repeated treatments with 10 g EMLA on a 7 x 5 cm large ulcer [39]. This patient, however, had a history of central retinal artery occlusion, cholestasis, atrial fibrillation and hypertension, and received a multitude of other medications, including buflomedil. Unfortunately no plasma samples of lidocaine and prilocaine were taken, but considering the results of studies of plasma concentrations in leg ulcer patients (see below) it seems unlikely that the accumulation of lidocaine and prilocaine was the reason for the seizures. The fact that the last 7 EMLA treatments had been given 2 to 3 days apart would ensure complete elimination of the local anaesthetics from the body between each dose, since the half-lives of lidocaine, prilocaine and the main metabolite are between 1.5 and 4 hrs in the elderly [40, 41]. Although a synergistic toxic effect of the local anaesthetics and buflomedil, which can all produce convulsions at overdoses, cannot be excluded, other causes of seizures such as epilepsy, acute seizures or Alzheimer's type dementia are also possible grounds for this event [42].

Pharmacokinetic studies

High plasma levels of local anaesthetics may produce symptoms of cardiovascular and central neural system toxicity. Five investigations have evaluated the systemic plasma levels of lidocaine and prilocaine after doses of 5-10 g EMLA applied to leg ulcers up to 100 cm² large. Three of these studies used EMLA 5% within the recommended application time range, 30-60 min. One study used prolonged exposure for 24 hrs [43], and the last study used a lower concentration than that currently in clinical use, EMLA 2%. Overall, the resulting maximum individual plasma concentrations of lidocaine did not exceed 839 ng/ml in any patient (Table IV). Prilocaine concentrations were considerably lower, maximum 277 ng/ml. This should be compared to the threshold for initial signs of CNS toxicity, 5-6,000 ng/ml of either agent [44]. Prolonged application for 24 hrs did not produce higher plasma levels than a 30-60 min application.

Repeated administration of 1-7 g EMLA one to three times a week for up to fifteen treatment sessions gave low plasma levels of both anaesthetics, well below the toxic threshold, with no apparent sign of accumulation of lidocaine or prilocaine or their main metabolites [20]. In the same study there was a significant correlation between the plasma levels of lidocaine and prilocaine and both the dose of EMLA and the leg ulcer area.

In summary, amounts of up to 10 g EMLA cream applied as a single or repeated dose to leg ulcers up to 100 cm² for 30 to 60 min produce systemic plasma levels well below the toxic threshold. The plasma levels are related to both the dose given and the ulcer area. Caution is therefore advised when administering EMLA to ulcers larger than 100 cm².

CONCLUSION

EMLA is the only topical anaesthetic for which there is clinical evidence of analgesic efficacy for ulcer debridement. Applied for 30-45 min in a dose of 1-2 g/10 cm², it significantly reduces the pain from sharp debridement, decreases the incidence of post-debridement pain and reduces the time needed to achieve a clean ulcer, offering potential savings in health care costs. EMLA also significantly reduces debridement pain in patients premedicated with oral analgesics, which are ineffective in preventing debridement pain when used alone. Doses of up to 10 g EMLA result in plasma levels of lidocaine and prilocaine well below toxic levels. Repeated treatment does not change the bacterial flora of the ulcer and rarely causes sensitisation.

The use of EMLA and possibly other long-acting amide topical anaesthetics for the relief of chronic ulcer pain deserves further study. The future may hold beneficial effects of such formulations on patients' long-term quality of life. Meanwhile, physicians and nurses should always be sensitive to the presence of chronic pain in leg ulcer patients and liberally prescribe oral analgesics.

REFERENCES

1. Callum MJ, Ruckley CV. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J 1995; 290: 1855-6.

2. Moffat CJ, O'Hare L. Venous leg ulceration: treatment by high compression bandaging. Ostomy/Wound Mgmt 1995; 41: 16-25.

3. Lindholm C, Bjellerup M, Christensen OB, Zederfeldt B. Quality of life in chronic leg ulcer patients. Acta Derm Venereol (Stockh) 1993; 73: 440-3.

4. Phillips T, Stanton B, Provan A, Lew R. A study of the impact of leg ulcers on quality of life: financial, social and psychologic implications. J Am Acad Dermatol 1994; 31: 49-53.

5. Noonan L, Burge SM. Venous leg ulcers: is pain a problem? Phlebology 1998; 13: 14-9.

6. Hofman D, Ryan TJ, Arnold F, Cherry GW, Lindholm C, Bjellerup M, Glynn C. Pain in venous leg ulcers. J Wound Care 1997; 6: 222-4.

7. Walshe C. Living with a venous leg ulcer: a descriptive study of patients' experiences. J Advanced Nursing 1995; 22: 1092-100.

8. Hansson C, Holm J, Lillieborg S, Syren A. Repeated treatment with lidocaine/prilocaine cream (EMLAs^®) a topical anaesthetic for the cleansing of venous leg ulcers: a controlled study. Acta Derm Venereol (Stockh) 1993; 73: 231-3.

9. Ryan TJ. Current management of leg ulcers. Drugs 1985; 30: 461-8.

10. Steed DL, Donohoe D, Webster MW, Lindsley L, and the Diabetic Ulcer Study Group. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. J Am Coll Surg 1996; 183: 61-4.

11. Vowden KR, Vowden P. Wound debridement, Part 2: sharp techniques. J Wound Care 1999; 8: 291-4.

12. Douglas WS, Simpson NB. Guidelines for the management of chronic venous leg ulceration. Report of a multidisciplinary workshop. British Association of Dermatologists and the Research Unit of the Royal College of Physicians. Br J Dermatol 1995; 132: 446-52.

13. Steele K. Pinchgrafting for chronic venous leg ulcers in general practice. J Royal Coll Gen Pract 1985; 35: 574-5.

14. Eriksson G. Leg ulcers. Diagnosis and treatment. Södertälje. Astra Pain Control AB, 1994.

15. Knighton DR, Ciresi K, Fiegel VD, Schumerth S, Butler E, Cerra F. Stimulation of repair in chronic, nonhealing, cutaneous ulcers using platelet-derived wound healing formula. Surg Gynecol Obstet 1990; 170: 56-60.

16. Dräger E, Winter H. Surgical debridement versus enzymatic debridement - benefits and drawbacks. In: Baharestani M, Gottrup F, Holstein P, Vanscheidt W, eds. The clinical relevance of debridement. Berlin Heidelberg: Springer-Verlag, 1999: 59-71.

17. Becker HD, Burg, Lanzius D, Meaume S, Stark GB, Sterry W, Téot L, Werner KG, Wolff K. Handlungsleitlinjen für die ambulante Behandlung chronischer Wunden und Verbrennungen. 1998: 11.

18. Mekkes J. Debridement of venous leg ulcers. Amsterdam: Academische Pers BV, 1998: 25.

19. Peschen M, Petter O, Vanscheidt W. Chronisch-venöse Insuffizienz - von der Pathophysiologie zur Therapie. Folge 4: Behandlung Des Ulcus Cruris - Therapierichtlinien. Fortschritte Der Medizin 1996; 114: 395-7.

20. Lok C, Paul C, Amblard P, Bessis D, Debure C, Faivre B, Guillot B, Ortonne JP, Huledal G, Kalis B. 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: 208-13.

21. Norwegian Medicines Control Authority, Oslo, Norway and Medical Products Agency, Uppsala, Sweden: Workshop. Treatment of venous leg ulcers. 1995; 5: 14-24.

22. Ryan TJ, Burnand K. Diseases of the veins and arteries: leg ulcers. In: Champion RH, Burton JL, Burns DA, Breathnach SM, eds. Textbook of Dermatology. 6th edition. Oxford: Blackwell Science, 1998: 2270.

23. Holst RG, Kristofferson A. Lidocaine-prilocaine cream (EMLA creams^®) as a topical anaesthetic for the cleansing of leg ulcers: the effect of length of application time. Eur J Dermatol 1998; 8: 245-7.

24. Juhlin L, Evers H. EMLA: a new topical anesthetic. Adv Dermatol 1990; 5: 75-92.

25. Rylander E, Sjöberg I, Lillieborg S, Stockman O. Local anesthesia of the genital mucosa with a lidocaine/prilocaine cream (EMLA) for laser treatment of condylomata acuminata: a placebo-controlled study. Obstet Gynecol 1990; 75: 302-6.

26. Holm J, Andren B, Grafford K. Pain control in the surgical debridement of leg ulcers by the use of a topical lidocaine-prilocaine cream, EMLA^®. Acta Derm Venereol (Stockh) 1990; 70: 132-6.

27. Enander Malmros I, Nilsen T, Lillieborg S. Plasma concentrations and analgesic effect of EMLA (lidocaine/prilocaine) cream for the cleansing of leg ulcers. Acta Derm Venereol (Stockh) 1990; 70: 227-30.

28. Barghorn A, Wagner G. Percutaneous anesthesia and leg ulcer debridement: Perkutane Anästhesie beim Debridement venöser Unterschenkeluzera. Phlebologie (Germany) 1994; 23: 161-3.

29. 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. Clinical dermatology in the year 2000. London, May 1990.

30. Ohlsen L, Grafford K, Evers H. EMLA cream as a topical anaesthetic for ulcer debridement and simultaneous split-skin grafting. Eur J Plast Surg 1994; 17: 277-82.

31. Rosenthal D, Murphy F, Gottschalk R, Baxter M, Lycka B, Nevin K. Using a topical anaesthetic cream to reduce pain during sharp debridement of chronic leg ulcers. J Wound Care 2001; 10 : 503-5.

32. Agrifoglio G, Domanin M, Baggio E, Cao P, Alberti AN, Borin F, Todini AR, Becchi G, Caserini M. EMLA anaesthetic cream for sharp debridement of venous leg ulcers. A double-blind, placebo-controlled study. Phlebology (accepted for publication).

33. Peschen M, Hackenjos K, Wiek K, Schöpf E, Vanscheidt W. Lidocain-Prilocain-Creme (EMLA^®) zur Oberflächen-anästhesie von venösen Ulzera vor Debridement durch CO₂-Laser. Phlebologie (Germany) 1997; 26: 120-3.

34. Scott J, Huskisson EC. Graphic representation of pain. Pain 1976; 2: 177-84.

35. Suhonen R, Kanerva L. Contact allergy and cross-reactions caused by prilocaine. Am J Contact Dermat 1997; 8: 231-5.

36. Van den Hove J, Decroix J, Tennstedt D, Lachapelle JM. Allergic contact dermatitis from prilocaine, one of the local anaesthetics in EMLA^® cream. Contact Dermatitis 1994; 30: 239.

37. Le Coz CJ, Cribier BJ, Heid E. Patch testing in suspected allergic contact dermatitis due to EMLA^® cream in haemodialyzed patients. Contact Dermatitis 1996; 35: 316-7.

38. Thakur BK, Murali MR. Emla cream-induced allergic contact dermatitis: a role for prilocaine as an immunogen. J Allergy Clin Immunol 1995; 95: 776-8.

39. Boulinguez S, Sparsa A, Bouyssou-Gauthier ML, Bedane C, Bonnetblanc JM. Adverse effects associated with EMLA cream used as topical anesthetic for the mechanical debridement of leg ulcers (letter to the editor). J Am Acad Dermatol 2000; 42: 146-7.

40. Nation RL, Triggs EJ. Lignocaine kinetics in cardiac patients and aged subjects. Br J Clin Pharmacol 1977; 4: 439-48.

41. Tucker GT. Pharmacokinetics of local anaesthetics. Br J Anaesth 1986; 58: 717-31.

42. Lok C. Adverse effects associated with EMLA cream used as topical anesthetic for the mechanical debridement of leg ulcers (letter to the editor). J Am Acad Dermatol 2000; 42: 147-8.

43. Larsson-Stymne B, Rotstein A, Widman M. An open clinical study on plasma concentrations of lidocaine and prilocaine after application of EMLA^® 5% cream to leg ulcers. Clinical dermatology in the year 2000. London, May 1990.

44. Covino BG, Wildsmith JAW. Clinical pharmacology of local anesthetic agents. In: Cousins MJ, Bridenbaugh PO, eds. Neural blockade in clinical anesthesia and management of pain. 3rd edition. Philadelphia: Lippincott-Raven Publishers, 1998: 97-128.