Neuropathic pain is a challenge in children with burn sequelae. Although relatively infrequent, the intensity and chronicity of neuropathic pain negatively impact functionality and quality of life. The use of 5% lidocaine medicated plaster has not previously been reported in children. We explored the effectiveness and safety of 5% lidocaine medicated plaster to treat neuropathic pain in children with burn sequelae.
Three-month prospective, uncontrolled study.
Corporation of Aid to Burned Children (COANIQUEM), a nonprofit pediatric burn rehabilitation center in Chile.
Fourteen pediatric patients with burn sequelae neuropathic pain.
Demographics, burn and pain evolution (type, intensity [using Wong-Baker FACES], and Douleur Neuropathique 4 [DN4]), and patient functionality. Plasma lidocaine levels were measured at 0, 12, 36, and 60 hours after treatment commencement.
Fourteen patients were evaluable for plasma lidocaine levels. Twelve patients were available for clinical assessment (two patients lost to follow-up) [mean (standard deviation)]: age, 11 years 7 months (2 years 6 months); weight, 45 kg (11.9 kg); burn evolution, 5 years 6 months (4 years); time between burn and pain onset, 3 years 6 months (3 years 2 months); time between pain onset and treatment, 5.1 months (4.8 months); lidocaine, between <⅛ and ½ plaster; initial pain intensity (FACES), 6.8 (1.6); final pain intensity, 0 in 11/12 patients; DN4, initial-6, final-2.3. All patients reported improved functionality. Plasma lidocaine levels were ≤27.45 ng/mL (>180 times below critical levels). No adverse reactions occurred.
These are the first published data suggesting that 5% lidocaine medicated plaster improves patient functionality, and is effective and safe for the treatment of neuropathic pain in pediatric patients with burn sequelae.
Burns represent a common and potentially devastating cause of injury and distress in children, most commonly as a result of thermal injury (scalds, contact, flame) . Furthermore, burns are a major source of pediatric morbidity and are associated with significant annual health care resource utilization; U.S. data show that approximately 10,000 children (aged <18 years) were hospitalized with burn-associated injuries in 2000, with related health care costs of >USD 200 million . Over recent decades in Chile, there has been a decrease in the burn rate; in 1993, the rate was 3,000/100,000 in children aged <15 years, and a 2001 study records a rate of 933/100,000 in the same population. Of this group, about 15% of patients require surgery and/or rehabilitation programs due to the severity of their burns; this equates to about 6,000 per year who require rehabilitation .
Pediatric patients with burn sequelae pose multiple challenges, among which the presence of chronic pain, and neuropathic pain is a problem that is often underdiagnosed and undertreated . Importantly, regardless of the cause or extent of the burn injury, all children with burns will experience pain . The intensity and chronic nature of the pain have an adverse effect on functionality and quality of life of patients and their families, and are associated with the onset of depression, a negative impact on psychomotor development, limited participation in everyday activities, and social exclusion—factors that are fundamentally important for every human being .
Pediatric burn pain management often focuses only on acute and procedural pain, such as that related to dressing changes, physiotherapy, or postoperative procedures ; the management of neuropathic burn pain is often overlooked. Moreover, pharmacological management strategies for neuropathic pain in children rely largely on the use of anticonvulsants, antidepressants, and clonidine . From the pathophysiological perspective, such pharmacotherapy is unsuitable for use in neuropathic pain associated with burn sequelae, as this is localized neuropathic pain in which membrane stabilization with these drugs does not involve the peripheral membrane channels that are mainly associated with this kind of pain. Moreover, these drugs act systemically, with frequent adverse effects, contraindications, and variable clinical results, with no evidence of efficacy in long-term treatment, exceeding the target of controlling localized neuropathic pain.
In adults, the use of 5% lidocaine medicated plaster has been shown, in numerous clinical studies, to be effective in localized neuropathic pain of varied etiology, including painful postherpetic neuralgia, diabetic neuropathy, surgical and nonsurgical trauma, low back pain with neuropathic components, and burns . To our knowledge, there is only one previous report on the use of 5% lidocaine plaster in adolescents with neuropathic scar pain, not due to burns, and the previous report does not present safety information .
The aim of this study was to validate the 5% lidocaine medicated plaster as a safe and effective treatment for neuropathic pain in children with burn sequelae and its effect on functionality. To the authors' knowledge, this is the first report of the use of the 5% lidocaine medicated plaster for neuropathic pain in children with burn sequelae.
Materials and Methods
This was a 3-month prospective, uncontrolled clinical trial conducted at the Corporation of Aid to Burned Children (COANIQUEM), Santiago, Chile. COANIQUEM (http://www.coaniquem.cl/) is a nonprofit pediatric burn rehabilitation center, which is a reference center for both the acute and rehabilitation management of burned children in Chile.
Inclusion criteria were as follows: males and females aged >6 years of age; bodyweight >20 kg; scar or graft with no open wounds, completely re-epithelialized; localized neuropathic pain in postburn scar or graft; and signed informed consent approved by the ethics committee.
Patients were excluded from the study if there was a history of psychiatric disorders, or if peripheral nerve injury was present (in order to isolate localized neuropathic pain from burn scars from other possible neuropathic pain conditions).
Clinical variables and plasma lidocaine concentrations were measured. Use of the 5% lidocaine medicated plaster was as recommended by the supplier: the plaster was applied for 12 hours, followed by 12 hours with no plaster, and this cycle was repeated until 3 months of observation had been completed. Each 10 cm × 14 cm plaster contains 700 mg (5% w/w) lidocaine. No other type of medicinal product (related to pain management or any other condition) was administered during the 3-month observation period.
Clinical variables assessed were as follows: patient demographics (age, weight, gender), details of the burn (type of management following injury, time since the burn occurred and onset of pain), the nature of the pain (type, intensity [assessed using the FACES], and Douleur Neuropathique 4 [DN4] pain rating scales), and the patient's functionality based on an open-ended question about the greatest pain-related limitation to daily activities. Patients were asked about adverse reactions at all visits, and the author recorded all information.
The Wong-Baker FACES Pain Scale is a validated pediatric-rating tool consists of an illustrative series of five color faces that depict increasing pain intensity on a 0–10 scale in increments of 2. The end points of the scale were explained as “no pain” and “very much pain”. Each child was asked to point to the face that best represented his/her current pain. The DN4 questionnaire, a clinician-administered assessment tool that identifies neuropathic pain characteristics, was developed and validated recently in France .
The medicated plaster was applied to the area of pain for 12 hours, and then removed to leave the next 12 hours without plaster. Plasma lidocaine levels were measured before application of the 5% lidocaine medicated plaster, and 12, 36, and 60 hours after application, using chromatography with detection by mass spectrometry.
No statistical analysis was performed as this was a descriptive, uncontrolled clinical study.
Fourteen patients were enrolled in the study in accordance with the inclusion and exclusion criteria. Clinical evaluation was incomplete for two patients because they failed (for unknown reasons) to attend checkups and could not be traced using the supplied contact details. Results are presented from serial plasma measurements in all 14 patients and full clinical follow-up in 12 patients (Table 0001).
Two patients lost to follow-up for clinical assessment had maximum plasma lidocaine concentrations (both at 36 hours) of 1.36 ng/mL and 8.20 ng/mL, respectively.
Patient placed the plaster on the foot (foot pain).
The 12 patients consisted of eight females and four males. The mean age was 11 years 7 months (standard deviation [SD]: 2 years 6 months; range: 8 years 1 month–16 years 2 months) (Table 0001), and the mean weight was 44.9 kg (SD: 12.4 kg; range: 25–63 kg). The original burn injury had occurred at an average age of 6 years 4 months (SD: 5 years 6 months). The site of injury was the lower limbs in seven cases (the foot [four cases]), the upper limbs in four cases (the hand [one case]), and the thorax in one case. Seven of the 12 patients had received a graft (Table 0001).
The time between the initial injury and the onset of pain was 3 years 6 months (SD: 3 years 2 months; range: 1 month–10 years 5 months), and the time between the onset of pain and the start of treatment was 5.1 months (SD: 4.8 months). The mean initial score was 7.0 (SD: 1.8) on the FACES scale, with a median of 6 by DN4. Fractions ranging from <⅛ to ½ of a lidocaine plaster (distribution shown in Table 0001) were used to cover the painful area completely.
Mean FACES scale scores decreased progressively over time (Figure 0001). At the end of the third month of treatment, all but one patient had a FACES score of 0; the exception had a FACES score of 2 (Table 0001). With regard to the DN4, values also decreased to a median of 2 by the end of the third month.
Based on an open-ended question about the greatest pain-related limitation to daily activities, all patients reported improved functionality (Table 0001). Improvements included increased sleep quality, ability to touch the originally affected burn area, increased mobility/activity (e.g., able to run and jump, play football), and rapidly decreased pain in the area of the original burn.
As presented in Table 0001 and Figure 0002, the analysis of plasma samples from the 14 children showed a maximum lidocaine concentration of 27.45 ng/mL. In nine patients, maximum plasma samples did not exceed 10 ng/mL. There was no detectable correlation between the size of the plaster applied and the plasma concentration.
No adverse reactions were recorded following the application of the 5% lidocaine medicated plaster.
The 5% lidocaine medicated plaster is efficacious in the neuropathic pain of varied etiology, such as painful diabetic neuropathy, postherpetic neuralgia, surgical and nonsurgical trauma, and low back pain with neuropathic components . However, all current clinical trials have been conducted in adults, and there is currently a lack of safety and efficacy data in pediatric patients.
Patients with burn sequelae experience chronic pain with neuropathic characteristics, although the exact frequency of neuropathic-like pain and associated symptoms after burn injury varies widely . The incidence of paraesthetic sensations has been reported in up to 82% of adult patients 1 year or more after burn injury ; other investigators report incidence rates for burn-associated chronic pain in adults of 36% and 52% . These estimates are probably biased because they involve referral centers that attract patients with complications, and surveys that are likely to be answered by patients experiencing pain. Patients with chronic pain have a higher prevalence of other associated conditions and reduced functionality, which limits their ability to cope independently. In the case of children, this entails an alteration to normal psychomotor development and learning ability. There are currently no data on the frequency of chronic and/or neuropathic pain in pediatric patients with burn sequelae. There is only one published report about the use of 5% lidocaine medicated plaster in adolescents, with scars not due to burns. This report shows good clinical results, but there is a lack of information regarding lidocaine plasma levels and safety data . At our center, unpublished studies with representative samples have found the frequency to be 7% for superficial burns and 18% for deep burns requiring grafts or progressing to hypertrophic scarring.
The absence of a pathophysiologically suitable treatment option for neuropathic pain from burn sequelae led us to evaluate the safety and efficacy of the 5% lidocaine medicated plaster in our patients with neuropathic pain in scars, as these represent a paradigm of localized peripheral neuropathic pain.
Patients aged >6 years were selected because, in our experience, pain assessment is less reliable in patients aged younger than 6 years of age. There is no universally accepted method for evaluating the intensity and characteristics of neuropathic pain in pediatric patients. However, our clinical experience suggests that using the validated Wong-Baker FACES scale is reliable, mainly for sensitivity to therapy-induced changes, and the DN4 is easily understood by patients and their parents. Moreover, pediatric patients prefer the FACES scale to a numeric one . Patients with psychiatric or emotional problems likely to become chronic pain sufferers were excluded, as this clinical phenomenon was beyond the scope of our study, which focused on neuropathic local pain.
Clinical follow-up was completed in 12 of the 14 patients, whereas two patients were lost to follow-up. All 12 evaluable patients had deep injuries, but only seven had received grafts (the other three patients had not received grafts due to incorrect initial assessment). It should be noted that these patients were referred to our center after the acute phase, so their detailed past history was unavailable.
The time of onset of pain after injury varied widely. In some cases, pain developed within the first 4 months, whereas in another case it took more than 10 years; nevertheless, this did not influence the Wong-Baker FACES score or the clinical outcome. Therefore, we believe that, regardless of the time period from initial burn injury to pain onset, tackling neuropathic pain (as determined by clinical features) is the correct approach and the appropriate way to care for patients. According to our observations, a phenomenon exists whereby pain treated successfully may recur. In fact, one patient in this current case series suffered a recurrence of pain 2 months after treatment ended (with a FACES score of 0); the recurrent pain was associated with dysmenorrhea. Due to the recurrence of pain, this patient underwent psychological tests, which proved normal (Rorschach and Luscher test). In other patients with neuropathic pain not belonging to this case series, we have recorded pain recurrence in association with appendicitis, sprained ankle (unrelated to the scar site), direct sun exposure, and pregnancy. We believe this phenomenon represents a neurological alteration (due to a change in membrane channel expression and/or a change in spinal modulation) that determines susceptibility to pain in response to insults that bear no direct relationship. We suspect that this may be the mechanism of the observed pain reduction effect of the 5% lidocaine medicated plaster, as this drug directly counters this hypothetical mechanism.
The time between pain onset and starting treatment also varied widely, although it was not comparable with the time of pain onset. In fact, the time course of pain reduction showed no difference between patients with longer and shorter latent periods.
The plaster was applied as recommended by the manufacturer, being divided into fractions according to the size of the painful area. The highest lidocaine plaster dose used (half a plaster per application) was in a male patient aged 10 years and weighing 31.5 kg. The maximum plasma lidocaine concentration recorded in this patient was <14 ng/mL. The next highest lidocaine plaster dose (one quarter of a plaster) and patient's weight (40 kg) was also in a male (aged 11 years 7 months), with a maximum plasma lidocaine concentration of 6.41 ng/mL (Table 0001).
Pain intensity decreased rapidly. After the first week of application, the mean FACES score had halved. Seven patients had a FACES score of 0 after 1 month, while by the second and third months the corresponding numbers of patients scoring 0 on the FACES scale were 8 and 11, respectively. One patient still scored 2 on the FACES scale at the end of the third month, but this decreased to a FACES score of 0 after the study period had ended. As the plasma lidocaine level in this patient was below the detectable limit (<0.5 ng/mL), we believe that this was probably because the pain was in the sole of the foot, where the skin is thicker.
DN4 scores also reduced progressively during the 3-month study period. It should be noted that, generally in patients with burn sequelae and scars, pruritus, one of the components of DN4, is common (over 80% depending on the stage to which the scar has progressed). In some cases beyond this study, pruritus corresponds to the inflammatory activity triggered by recent scars, but in other cases it occurs when the scar shows no inflammatory activity, proves refractory to standard pharmacological and nonpharmacological management, and appears quite some time after the original injury, as with pain. We believe that, in these cases, chronic pruritus has neuropathic features, and we have preliminary unpublished experience of using the 5% lidocaine medicated plaster with good results. Nevertheless, we have not observed any adverse effect, including pruritus, during the utilization of lidocaine plaster in this study.
It is well accepted that patient functionality and quality of life are adversely affected by the intensity and chronic nature of pain resulting from burn injury, resulting in limited participation in everyday activities, social exclusion, and increased rates of depression . In a final assessment for patients, their families, and clinicians, these factors must represent the most important concerns of any involved in burn management programs. After 3 months of treatment with the 5% lidocaine medicated plaster, all patients in our study reported improvements in terms of functionality; patients experienced rapidly decreased pain in the area of the original burn, improved mobility/activity, the ability to touch the originally affected burn area, improved sleep quality, and a return to their normal lifestyles. There are many instruments for rating functionality, both generic and specifically for burns patients and pain sufferers; we used an open-ended question about the greatest pain-related limitation or inconvenience to daily activities, and how this evolved with treatment. This approach is more widely applicable clinically and is considered important by patients.
Plasma analysis showed that the highest lidocaine concentration was 27.45 ng/mL, in the 12-hour sample from a female patient with a painful area located in the arm. All plasma lidocaine concentrations were well below concentrations reported to be associated with arrhythmias or systemic toxic effects. Concentrations were also much lower than those achieved with other topical lidocaine formulations (such as eutectic mixture of lidocaine and prilocaine [EMLA]). The absence of systemic and local adverse effects (not even pruritus at the plaster application site) suggests that the 5% lidocaine medicated plaster may be a safe option for pain relief in the target population, although much larger studies are needed to establish safety. Nevertheless, it is important for clinicians to be alert to any potential future complications in the adult population in order to extrapolate this hypothetical situation to the pediatric population.
The 5% lidocaine medicated plaster appears to be safe and effective for use in patients aged >8 years with neuropathic pain characteristics resulting from burn injuries; to date, it is the only option for local therapy without using systemic drugs. Future studies, comparing the 5% lidocaine medicated plaster with placebo and conventional drugs, are required in order to further confirm its effectiveness and safety in children.
The authors thank David P. Figgitt, PhD, Content Ed Net, for providing valuable editorial assistance in the preparation of the manuscript. Editorial assistance was funded by Grünenthal GmbH, Aachen, Germany. The authors also thank Dr. Cristina Gastó, Grünenthal Chilena Ltda., and Dr. Ingrid Tacken, Grünenthal GmbH, Aachen, Germany, for study medication supply and scientific discussion.