Onset time of topical analgesia with EMLA 5%: no reduction with glyceryl trinitrate

Abstract

Many adults are distressed by painful investigations or treatment, including venepuncture. The early effects of Eutectic Mixture of Local Anaesthetics (EMLA) 5%, on relief of pinprick pain in the antecubital area was investigated and compared with EMLA plus glyceryl trinitrate and with a placebo cream in 100 patients. Topical analgesia after application of EMLA developed within 5 min in 69% and within 10 min in 83% of those tested, significantly different from placebo, (P = 0.01).

Introduction

It is commonly believed that the insertion of a small intravenous cannula is not painful ^[1]. In reality, both adults and children are distressed by any clinical investigation or treatment that may be painful. Pain and relief of pain were among topics of most importance to patients in one study ^[2]. Over one third of patients in another study expressed anxiety about injections before operation ^[3]. Anxiety is related to skin conductance which can be measured, and large increases have been found before general anaesthesia ^[4]. Nevertheless, induction of anaesthesia by the intravenous route has been reported as the preferred method in 91% of cases ^[5]. Lignocaine 10% gel with an absorption promoter ^[6] and amethocaine ^[7] both reduce the pain of venepuncture, while iontophoresis using lignocaine and adrenaline can also reduce pain occurring on subsequent injection of intravenous drugs ^[8]. EMLA 5%, a topical anaesthetic cream containing lignocaine 25 mg g⁻¹ and prilocaine 25 mg g⁻¹ in a water-miscible base (Astra, Kings Langley, UK), penetrates intact skin producing effective analgesia ^[9,10] but frequently causes vasoconstriction, blanching ^[11], making venous access difficult. Prior application of glyceryl trinitrate (GTN) has been shown to overcome the problem ^[12]. This study was devised to establish the rate of onset of topical analgesia with EMLA and to determine whether the time required would be changed by addition of a vasodilator.

Patients and methods

One hundred patients, ASA I or II, admitted to hospital for routine investigation or minor operations agreed to take part in a double-blind, randomized, within-patient, placebo-controlled trial. Ethical committee approval was obtained. They were allocated between three groups using random number tables. In group A, EMLA approximately 0.5 mL was compared to 0.5 mL placebo (aqueous cream, B.P.). In group B, a similar amount of EMLA was compared with EMLA mixed 1:2 by volume immediately before use with glyceryl trinitrate 2% ointment, Percutol (Cusi, Haslemere, UK). In group C, similar amounts of the EMLA/GTN mixture and placebo were compared. Each preparation was taken from an identical container and spread uniformly over a 5 cm wide area of either the right or left antecubital fossa using a clean wooden spatula. The side and order of application were randomized. An individual clock was started as soon as each area was treated. The observer, previously out of sight, then tested for loss of pinprick sensation using a card leaf-spring device with a sterile 21 s.w.g. needle (Becton Dickinson, Cowley, UK) fitted at slot X, (Fig 1). With arms extended and relaxed, the point of the needle was applied five or six times near possible venepuncture sites at intervals of about 20 s. Deflection of the 'leaf' by 2-3 mm was equivalent to pressure of 0.9-1.4 g. Patients were asked to say when they became aware of a definite change in sensation from sharp pinprick or 'pain' to a feeling of numbness or only 'touch'. A new needle was used for every patient. The corresponding clock was stopped when a change was reported, up to a maximum of 10 min.

Fig. 1: Test device, thin card (postcard) with needle at X.

The difference in time in seconds to loss of pinprick sensation between placebo cream and EMLA was obtained for each patient in group A. Positive difference showed that EMLA was more effective and negative meant that placebo was more effective. If EMLA was beneficial overall, then the mean of these differences would be positive. This was tested statistically using the Wilcoxon signed rank test. A nonparametric test of significance was used because the differences could not be assumed to be Normally distributed. Some patients failed to report numbness within 10 min for either placebo or EMLA. These observations were included as 10 min in the analysis. The effect of this is, at worst, to underestimate the effect of EMLA. A similar calculation was made for each of the paired treatments in patients of groups B and C. Statistical analysis was performed using STATA ^[13]. P = 0.05 was regarded as significant.

Results

The patients were aged between 16 and 92 years. There were 52 men and 48 women. Seven men and two women said that they were naturally left-handed. Patient characteristics and the findings in each group are given in Table 1.

Table 1: Patient related data and findings

The time to loss of pinprick sensation with EMLA was significantly shorter than the time using placebo, a mean difference of 37.6 s, P = 0.01. Six patients in this group reported no change for either preparation. The differences between the times to analgesia with placebo and with EMLA for each of the remaining 29 patients in group A are shown in Fig 2. The differences are not evenly distributed around zero; there is a clear shift towards a shorter time with EMLA. The percentages of patients reporting loss of pinprick sensation at one min intervals up to 10 min, derived from the observed data in this group, are given in Table 2. Five min after treatment with EMLA, the proportion of patients reporting numbness was 69%, (95% confidence interval, 53-84%). Neither age nor gender were significant.

Fig. 2: Within-patient differences between times to reported analgesia for placebo and EMLA.

Table 2: Percentage of patients numb to pinprick at 1 min intervals after application of EMLA, with 95% confidence interval (CI)

There was no significant difference between the EMLA/GTN mixture and EMLA in group B, mean 9.7 s, P = 0.21. In this group, as in group A, the number of patients reporting analgesia after EMLA increased with application time. In group C, the mean difference between EMLA/GTN and placebo was 29.0 s, P = 0.06. Transient capillary vasoconstriction was seen in all groups. It was noticed that analgesia could sometimes be preceded by hypersensitivity.

Discussion

The question most often asked is how long does EMLA take to work? We have demonstrated that after topical application of EMLA, the proportion of patients reporting analgesia to pinprick increases with time, reaching 83% within 10 min. This confirms previous studies in patients undergoing venepuncture ^[14] and observations with subcutaneous needle insertion in volunteers ^[15]. Venous cannulation causes a stretching as well as cutting injury and is known to be more painful ^[1].

It was vital for the study to be securely blind. Both side and order of application were randomized to offset any effect of one treatment on another, each clock was started at an arbitrary point so that the observer was unaware of the exact timing and all data were logged separately until the conclusion of the trial. Each patient acted simultaneously as their own control, a method described in only one other report ^[17]. A single anatomical position was chosen because pain measurements can differ between various sites ^[7] and with intravenous injection ^[8]. Pinprick testing was used because the same size needles as required for later blood samples could be employed. Other methods of testing skin sensitivity include laser stimulation ^[16] and use of a semi-sharp 0.8 mm diameter steel pin (Owen Mumford, Oxford, UK) but pinprick near a suitable vein was considered satisfactory for the response to potential venepuncture. The range of differences in time to numbness shows the strength of the placebo effect, with the most extreme subject reporting almost immediate loss of pinprick sensation, then a delay of 3 min until numbness with EMLA. This patient was the oldest in the study.

Local anaesthesia after EMLA for 30 min has been shown to be inadequate ^[18], requiring 45 min before cannulation is painless ^[10]. Furthermore, no effort was made to evaluate possible analgesia. The chance that analgesia might be caused by fatigue from multiple stimuli within a small area was minimized by testing at intervals of 20 s ^[16], which would tend towards an overestimation of the elapsed time, whereas testing with a hollow needle might allow penetration or direct deposition of EMLA to contribute to the effect, and have led to underestimation. Either way, a distinct difference between the response to EMLA and placebo was found. Blanching, seen frequently, may be the action of EMLA on vascular smooth muscle or an effect mediated by the nervous system ^[11]. Vasoconstriction can make venepuncture difficult. However, we found that the deeper veins were always easily distended after EMLA was applied for these short periods even though blanching was evident. The addition of GTN to EMLA did not shorten the onset time, suggesting that rapid development of analgesia is associated with a reduction in vascular uptake ^[19]. We found the area of treatment needed to be somewhat large, perhaps related to an overall reduction of sensory input ^[20].

Many attempts have been made to reduce the pain of injections, because they hurt and patients do not like it! ^[21]. A high-velocity jet (Panjet, Schuco International, UK) and a spring-loaded autoinjector (Glaxo, UK) have been used to 'shoot' local anaesthetics through the skin thus preventing injections altogether. The advantage of avoiding pain in children is said to be self-evident ^[22] and a disposable patch containing EMLA 2.6 g is now available for them ^[23]. Why not also for adults, who may be even more fearful of needles? Many are surprised when they are not hurt as they expect, and will often co-operate more readily. A patient's first experience in hospital or operating theatre need no longer be painful venepuncture ^[24].