Introduction
The 5% lidocaine-medicated plaster has been used for several years to treat localized neuropathic pain (LNP) and reviews of published studies support its use in this indication [
1,
2]. Topical application offers a number of advantages over systemic administration. For example, systemic levels of topical analgesic agents are low—with 5% lidocaine-medicated plasters, only 3% ± 2% of the dose reaches the systemic circulation [
3] so the risk of drug–drug interactions, systemic side effects and overdose is much reduced [
4]. This increased safety margin is important because the response to prescribed medication can vary widely between patients, often as a result of polymorphisms [
5], and it is particularly relevant for vulnerable patients such as the elderly and those receiving polypharmacy for multiple co-morbidities. From a practical aspect, the topical route offers simple site-specific delivery by the patients themselves to the most painful areas, without the need for dose titration [
6], and the act of application may increase the placebo element of analgesia [
7].
To date, the 5% lidocaine-medicated plaster (Versatis
®, Grünenthal GmbH, Aachen, Germany) has been registered in approximately 50 countries around the world. In the majority of these countries, it is licensed only for relieving neuropathic pain caused by postherpetic neuralgia (PHN), but in 11 Latin American countries it has been approved for treating LNP. The total cumulative patient exposure to 5% lidocaine-medicated plaster since marketing authorization was first obtained in 1999 has now reached approximately 23 million patients. Its efficacy and safety in treating PHN have led to widespread use in other LNP syndromes, including diabetic distal polyneuropathy, post-surgical, and post-traumatic pain [
1].
A number of researchers and reviewers have recommended the lidocaine plaster as a first-line option for treating LNP [
2,
8‐
15], because the benefit-to-risk ratios are far better than those of systemic analgesic agents [
16,
17]. At the present time, the management of patients with neuropathic pain is often inadequate [
18,
19], and many patients are not satisfied with their treatment [
20,
21]. The objective of this article is to examine the inclusion of the 5% lidocaine-medicated plaster in international treatment guidelines and the body of evidence currently supporting its use, so that this pharmacological option may be considered more often by clinicians treating patients with LNP.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.
The 5% Lidocaine-Medicated Plaster
Lidocaine is a voltage-gated sodium channel inhibitor, which is understood to act by blocking abnormally functioning (sensitized) Nav1.7 and Nav1.8 sodium channels in the dermal nociceptors of A delta and C fibers, thereby reducing the number of ectopic discharges [
22‐
24]. However, it is also effective in patients where nociceptive function is impaired [
25]. This is probably due to an inhibitory effect on inflammatory processes, as lidocaine has been shown to regulate T cell activity and suppress the production of nitric oxide [
26,
27]. Another probable mechanism is direct activation of the TRP (transient receptor potential) channels TRPV1 and TRPA1 expressed in nociceptive sensory neurons. This produces analgesia by membrane depolarization, reducing the electrical activity in TRP-containing nerves [
28].
Each 5% lidocaine-medicated plaster measures 10 × 14 cm and consists of a white hydrogel adhesive containing lidocaine (700 mg, 5% w/w) attached to a non-woven polyethylene terephthalate backing [
29]. The plaster is applied once daily to intact, dry, non-irritated skin and worn for a maximum of 12 h. Up to three plasters may be applied simultaneously, depending upon the size of the painful area, and the subsequent plaster-free period must be at least 12 h [
29]. Where appropriate, plasters may be cut to match the shape of the painful area. Application provides mechanical protection and a sensation of immediate cooling (the ‘patch’ effect) [
30]. Steady-state plasma concentrations of lidocaine are reached within the first 4 days [
29], but the maximum concentration remains far below clinically relevant levels even when the recommended dose is exceeded [
31]. After extensive metabolism in the liver, mainly by N-alkylation, the excretion of lidocaine and its metabolites is primarily via the kidneys [
29]. Less than 10% of the lidocaine dose is excreted unchanged [
29]. The elimination half-life in healthy individuals is 7.6 h, but may be delayed in the presence of cardiac, renal, or hepatic insufficiency [
29]. Treatment should be reassessed at regular intervals to determine whether the number of plasters can be reduced, or the plaster-free period extended [
29].
Treatment with the lidocaine plaster is generally well tolerated and markedly improves patients’ quality of life [
1]. The most frequently reported adverse events are mild-to-moderate reactions at the application site, including erythema, pruritus, rash, burning sensation, edema, and other skin reactions [
9,
17,
32]. These adverse events are generally transient and resolve without further treatment once the plaster is removed [
17]. Furthermore, the excellent safety profile continues with long-term treatment. In an open-label study lasting up to 4 years, medication was rated as ‘good’ or better by 88% of patients and only 18.6% experienced adverse events that could be related to their treatment [
33]. Another group of patients with chronic refractory neuropathic pain caused by postherpetic neuralgia was surveyed after using the lidocaine plaster daily for a mean period of 7.6 years [
34]. Using an 11-point numerical rating scale (NRS) on which a score of +5 represented ‘Extremely Satisfied’ and −5 ‘Extremely Dissatisfied’, mean satisfaction with pain relief was rated at +3.8, mean overall satisfaction at +4.0, and 75% of the patients reported having had no adverse events [
34].
Neuropathic Pain and LNP
Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” [
35,
36]. Population-based surveys in the United Kingdom and France have found the prevalence of pain with predominantly neuropathic characteristics to be 8% and 6.9%, respectively [
37,
38]. Currently, expert opinion is that neuropathic pain arises from damage to somatosensory small fibers rather than non-nociceptive pathways [
39,
40]. The origin may be central or peripheral, and neuropathic pain is a feature of many different conditions. The most common symptoms are continuous burning pain, paroxysmal ‘electric shock’ or lancinating pain, and allodynia [
40‐
42]. Burning pain reflects spontaneous hyperactivity in nociceptive C-fiber pathways, which may originate from (1) ‘irritable’ nociceptors (i.e., that have increased excitability as a result of peripheral sensitization, mainly produced by changes in voltage-gated sodium channel expression [
43]), (2) hyperexcitable regenerating nerve sprouts, or (3) denervated central neurons [
40]. Paroxysmal pain probably arises from high-frequency ectopic bursts generated in demyelinated, non-nociceptive Aβ fibers [
40]. Mechanical dynamic allodynia is mediated by non-nociceptive Aβ fibers activating central pain pathways, but ‘irritable’ C-nociceptors probably contribute to the maintenance of allodynia and to central sensitization in peripheral neuropathies [
40].
Evidence suggests that herpes zoster and peripheral nerve traumas are the most frequent causes of peripheral neuropathic pain, whereas stroke, multiple sclerosis and spinal cord injury are the major causes of central neuropathic pain [
44‐
47]. The negative impact upon functioning and quality of life is profound [
48,
49]. Studies have demonstrated that neuropathic pain is more severe than non-neuropathic pain [
50], it is associated with an excessive psychosocial burden compared with nociceptive pain, and it can induce more intense psychological comorbidity than other types of chronic pain [
48,
50,
51].
Although neuropathic pain may be widely distributed, in approximately 60% of patients it affects a specific, clearly demarcated area of the body [
52] and may be described as ‘localized neuropathic pain’ (LNP). In order to help clinicians distinguish LNP from other types of neuropathic pain, a body of experts proposed the following definition of LNP in 2010, based upon the IASP definition of neuropathic pain and 13 reference articles: ‘A type of peripheral neuropathic pain that is characterized by consistent and circumscribed area(s) of maximum pain associated with abnormal sensitivity of the skin and/or spontaneous symptoms characteristic of neuropathic pain, for example, burning pain’ [
52]. By identifying patients with LNP—who may benefit from topical treatment—this definition facilitates an evidence-based approach to the management of neuropathic pain. It should be pointed out that topical treatment refers to pharmaceutical agents that act locally on the peripheral nervous system, in contradistinction to medications such as buprenorphine and fentanyl that may be applied to the skin but which exert their effect on the CNS following transdermal systemic absorption [
7].
LNP Treatment Guidelines-Positioning of the 5% Lidocaine-Medicated Plaster
Most clinical evidence on the efficacy of the 5% lidocaine-medicated plaster—and most guidelines—relate to the treatment of PHN, owing to its being more widely licensed for this condition, and the comparatively recent definition of LNP.
For its 2004 guidelines, reaffirmed in 2010, the Quality Standards Subcommittee of the American Academy of Neurology examined 51 articles on therapies for treating PHN [
53]. The following parameters were calculated for each study using intent-to-treat analysis: absolute risk reduction (proportion of control group with benefit minus proportion of treated group with benefit); number needed to treat (NNT) for adequate pain relief; 95% confidence interval for the NNT; and number needed to harm (NNH). A score was then determined for each therapy based upon the quality of the studies (e.g., Class I evidence was provided by a prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population). On the basis of these criteria, the 5% lidocaine-medicated plaster was placed in the top treatment category for PHN, along with gabapentin, oxycodone or morphine sulphate, pregabalin and tricyclic antidepressants (TCAs) [
53]. These were all considered to offer medium-to-high efficacy, good strength of evidence supporting their use, and a low level of side effects [
53].
Evidence-based recommendations for the treatment of neuropathic pain were first published by the Neuropathic Pain Special Interest Group (NeuPSIG) of the IASP in 2007, following a consensus meeting [
8]. Initially, relevant publications were identified through Medline literature searches (1966–2007), reference lists of published articles and book chapters, and personal knowledge of the authors. This published material, along with unpublished data and the authors’ clinical experience, was then used to evaluate various medications in terms of efficacy, safety, tolerability, drug interactions, ease of use, and impact on health-related quality of life [
8]. Having demonstrated efficacy in PHN and diverse peripheral neuropathic pain conditions, the 5% lidocaine-medicated plaster was recommended as a first-line treatment for peripheral neuropathic pain, but not for central neuropathic pain [
8]. These recommendations were later reviewed and updated by NeuPSIG in 2010, after more clinical trials had been completed [
11]. Group members concluded that adherence to the existing guidelines should be improved for the time being, while additional randomized, controlled trials directly comparing neuropathic pain medications were conducted and alternative evaluative strategies were developed [
11].
Later in 2010, recommendations on the pharmacological management of neuropathic pain were published by Attal et al. [
54]. These recommended topical lidocaine as a first-line treatment for PHN, commenting on its excellent tolerability and noting that all recommendations for the pharmacological treatment of neuropathic pain at that time proposed antiepileptics (gabapentin or pregabalin), TCAs, serotonin–noradrenaline reuptake inhibitors (SNRIs) or topical lidocaine as the first line of treatment for neuropathic pain in general, or for specific neuropathic pain conditions [
54].
Narrower terms of reference were used by the European Federation of Neurological Societies (EFNS) Task Force to produce its guidelines, which were first published in 2006 [
55] and updated in 2010 [
13]. The Cochrane Database and then Medline were searched for relevant studies, which were subsequently classified according to the etiological condition investigated. All EFNS Class I and Class II randomized controlled trials were assessed, with lower class studies being considered in conditions for which there were no top level studies. NNT values and their corresponding 95% confidence intervals were calculated in order to provide information about the overall efficacy of analgesic agents [
13,
55]. The earlier guidelines considered that there was insufficient evidence to confirm the efficacy of the lidocaine plaster, but stated that it may be preferred to other agents when treating PHN–particularly in patients with allodynia and a small area of pain—because of its excellent tolerability [
55]. The inclusion of additional trials in the 2010 update provided some good evidence of efficacy, although trial results were inconsistent. Consequently, the updated guidelines stated that the 5% lidocaine-medicated plaster may be considered a first-line treatment in the elderly, particularly if there are concerns regarding the CNS side effects of oral medications [
13].
A new, more rigorous and generally accepted methodology (GRADE—Grading of Recommendations Assessment, Development, and Evaluation) was adopted for the 2015 revision of the NeuPSIG guidelines [
56]. GRADE classifies the quality of evidence as high, moderate, or low according to various factors, including the risk of bias, precision of estimates, consistency of results, and directness of evidence [
57]. A strong recommendation for use is given only when the benefits of an intervention clearly outweigh the undesirable effects [
57]. A systematic review and meta-analysis were conducted of randomized, double-blind studies of pharmacotherapy for neuropathic pain, as well as unpublished trials retrieved from ClinicalTrials.gov and the Web sites of pharmaceutical companies [
56]. The NNT for 50% pain relief was used as the primary outcome measure, and publication bias was assessed. Stringency of the GRADE criteria meant that only three trials of the lidocaine plaster were included, so that the quality of assessed evidence was low. Thus, only a weak recommendation for use was made, as a second-line treatment for peripheral neuropathic pain with presumed local pain generator (such as PHN), post-traumatic painful neuropathies and polyneuropathies [
56]. However, it was acknowledged that in certain circumstances, such as concern about side effects or the safety of first-line options, particularly in frail and elderly patients, the 5% lidocaine-medicated plaster might be a first-line option [
56].
Also in 2015, an international advisory board of pain specialists, selected on the basis of their research activity and considerable clinical experience, met to develop a treatment guidance algorithm specifically for LNP, to be used in the primary care setting [
15]. It was generally felt that existing guidelines were of limited use in determining treatment for LNP, because most do not specifically address this condition—or even recognize it as a specific entity—and recommendations of the different guidelines are not consistent [
15]. Board members strongly agreed that the first-line treatment—irrespective of age—should be a topical analgesic agent in most cases unless there are contraindications such as broken, atrophic, or infected skin—essentially because the topical route offers a far better safety profile [
16,
17] and there is evidence that it can reduce the size of the painful area [
58‐
60]. Factors influencing the choice of topical agent should include ease of application and use, patient preference, and availability [
15], but the 5% lidocaine-medicated plaster currently has the most evidence supporting its use in treating LNP.
Discussion
There is mounting evidence of the efficacy of the 5% lidocaine-medicated plaster in studies conducted in everyday clinical practice, which represents a considerable proportion of actual usage. Many of these studies suggest using the lidocaine plaster as a first-line treatment for LNP, but this is not always reflected in national and international guidelines. There are various reasons for this.
Guidelines for analgesic agents are generally based on the results of randomized, double-blind, placebo-controlled clinical trials using the NNT for a defined level of pain relief as the measure of efficacy. In a review of 105 randomized, double-blind, placebo-controlled trials in patients with neuropathic pain, for example, the 5% lidocaine-medicated plaster had an NNT of 4.4, comparable to antidepressants (1.2–6.9) and anticonvulsants (1.4–7.4) [
36].
However, many trials of the lidocaine plaster used the time to withdrawal to indicate efficacy, for which it was not possible to calculate NNTs. These trials were therefore excluded when drawing up the guidelines, thereby weakening the body of evidence for the 5% lidocaine-medicated plaster.
Furthermore, the value of NNTs in the development of guidelines is limited on several counts [
2]. Firstly, reliable NNT data from multiple studies can only be obtained where these are parallel-designed, placebo-controlled studies with comparable inclusion and exclusion criteria [
2,
86]. The statistical design of the lidocaine plaster trials varied from study to study, as did the maximum dose—from less than one plaster to three plasters. Secondly, NNTs are primarily derived from patients’ VAS evaluations of pain, which researchers now recognize may be inappropriate, so that other criteria (patient global impression of pain improvement, psychosocial functioning, activities of daily living, gait, quality of life) are used to provide a more complete assessment of analgesic efficacy [
2]. Therefore, any NNT data would have been of limited benefit. Further limitations are that non-placebo-controlled trials were excluded and efficacy was generally based on a one-dimensional measure of pain intensity or pain relief, so a statistically significant advantage could not necessarily be translated into a clinically relevant benefit.
In the case of the 2015 NeuPSIG guidelines, another consideration is that studies with an enriched enrolment design were analyzed separately, despite the fact that these can be useful in determining the efficacy of a medication compared to placebo; there appears to be no difference between enriched and non-enriched studies when measuring this parameter [
87,
88]. A meta-analysis of 26 enriched enrolment, randomized withdrawal (EERW) trials in over 5000 patients with chronic non-cancer pain concluded that these trials ‘if properly designed, conducted, and reported, are entirely appropriate in the context of chronic pain for explaining whether a treatment is efficacious, and for pragmatically supporting decisions over its use’ [
88]. Some authors have even contended that the available guidelines have very little clinical application to daily practice because multimodal therapy is widely considered the treatment of choice for LNP, but evidence-based data on this approach is lacking [
89].
The excellent tolerability of the 5% lidocaine-medicated plaster, its lack of ADRs, and low potential for drug–drug interactions, are widely recognized. This is a particularly important consideration when treating elderly and/or frail patients, or those receiving multiple medications. Both the EFNS and 2015 NeuPSIG guidelines recognize these benefits, stipulating that the lidocaine plaster may be considered a first-line option for these patients [
13,
56]. Furthermore, its safety profile and ease of use can significantly increase patients’ adherence to chronic treatment, with consequent benefits on efficacy and quality of life [
33].
Taking a wider perspective, a number of studies have recorded significantly better quality of life (QoL) scores following commencement of treatment with the lidocaine plaster. For example, in one large, open-label effectiveness study in patients with PHN, the mean pain interference with QoL significantly decreased in all domains of the Brief Pain Inventory Short Form (general activity, mood, walking, working, relations, sleeping, enjoyment) after 7, 14, and 28 days’ treatment (
p < 0.0001) [
70]. Similarly, when 56 patients with painful diabetic polyneuropathy were treated for 3 weeks (up to four plasters/day for 18 h), significant improvements were seen in sleep quality, interference of pain with daily activities, depression, and mood [
90]. More recently, a 2012 study used the QoL Impairment by Pain Inventory (QLIP) to evaluate the perceptions of over 900 patients with chronic neuropathic pain who received treatment with the lidocaine plaster [
91]. QLIP measures well-being, sleep, pain, impairments, and mood, the maximum score of 40 points reflecting minimal interference with daily life. Over the 12 weeks of the study, the mean QLIP score increased from 13.7 to 35.2 [
91].
Allodynia is often a prominent feature of LNP, and is usually considered to be one of the most distressing and debilitating symptoms of PHN [
92,
93]. Therefore, one contributory factor to the improved QoL scores is likely to be the reduction in the area of allodynia—typically more than 50% [
59,
60]—produced by treatment with the lidocaine plaster. Reducing the painful area, which can increase tolerance of bathing and contact with clothing, is therefore a justifiable treatment goal for this medication. When the painful area is on the sole of the foot—limiting mobility—or on the palm of the hand, this advantage of the topical route and the 5% lidocaine-medicated plaster over systemic medications assumes even greater importance [
58].
Acknowledgements
Sponsorship for this article and article processing charges were funded by Grünenthal GmbH of Aachen, Germany.
All named authors meet the International Committee of Medical Journal Editors (ICJME) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Editorial assistance in the preparation of this manuscript was provided by Derrick Garwood of Derrick Garwood Ltd, Cambridge, United Kingdom. Support for this assistance was funded by Grünenthal GmbH.
Disclosures
Ralf Baron has received grants/research support from Pfizer, Genzyme GmbH, Grünenthal GmbH and Mundipharma. He is a member of the EU Project No 633491: DOLOR-isk. He is a member of the IMI “Europain” collaboration and industry members of this are: Astra Zeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal GmbH, Eli Lilly and Boehringer Ingelheim Pharma GmbH & Co. KG. German Federal Ministry of Education and Research (BMBF): member of the ERA_NET NEU-RON/IM-PAIN Project, German Research Network on Neuropathic Pain, NoPain system biology and German Research Foundation (DFG). He has received speaking fees from Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co. Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD GmbH, and Seqirus. He has been a consultant for Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Allergan, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co. Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Astellas, Novartis, Bristol-Myers-Squibb, Biogenidec, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus, Teva Pharma, Genentech, and Galapagos NV. Massimo Allegri has received honoraria from Angelini, CareFusion, Grünenthal GmbH, MSD, and Mundipharma, and a research grant from the European Union. Gerrardo Correa-Illanes has acted as a medical advisor to Grünenthal GmbH, LATAM Airlines Group, and Global. Guy Hans has nothing to disclose. Michael Serpell has received honoraria from Astellas, Grünenthal GmbH, NAPP, and Pfizer for speaking at meetings. His institution has received research support in the past 5 years from commercial studies sponsored by Astellas, Grünenthal GmbH, and NAPP. Gerard Mick has received honoraria from Grünenthal GmbH, Mundipharma, Pfizer and Astellas. Victor Mayoral has received honoraria and fees for the provision of expert opinion from Grünenthal GmbH, Mundipharma, Menarini, Archimedes Pharma, Takeda and Ferrer.