This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the analgesic efficacy of topical lidocaine for chronic neuropathic pain and fibromyalgia in adults
To assess the adverse events associated with the clinical use of topical lidocaine for chronic neuropathic pain and fibromyalgia
This protocol is based on a template for Cochrane systematic reviews of drugs used to relieve neuropathic pain. The aim is for all reviews to use the same methods, based on new criteria for what constitutes reliable evidence in chronic pain (Moore 2010a; Appendix 1). An earlier review of topical lidocaine for postherpetic neuralgia has been withdrawn from the Cochrane Library because it was out of date (Khaliq 2007); the topic will be covered within the broader scope of this review.
Description of the condition
The 2011 International Association of the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011), based on an earlier consensus meeting (Treede 2008). Neuropathic pain may be caused by nerve damage, but is often followed by changes in the central nervous system (CNS) (Moisset 2007). It is complex (Apkarian 2011; Tracey 2011), and neuropathic pain features can be found in patients with joint pain (Soni 2013). Many people with these conditions are significantly disabled with moderate or severe pain for many years.
Chronic painful conditions comprise five of the 11 top-ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life, employment, and increased health costs (Andrew 2014).
In primary care in the UK the incidences, per 100,000-person years observation, have been reported as 28 (95% confidence interval (CI) 27 to 30) for postherpetic neuralgia, 27 (95% CI 26 to 29) for trigeminal neuralgia, 0.8 (95% CI 0.6 to 1.1) for phantom limb pain and 21 (95% CI 20 to 22) for painful diabetic neuropathy (Hall 2008). Estimates vary between studies, often because of small numbers of cases. The incidence of trigeminal neuralgia has been estimated at 4 in 100,000 per year (Katusic 1991; Rappaport 1994), while more recently, a study of facial pain in the Netherlands found incidences per 100,000-person years of 12.6 for trigeminal neuralgia and 3.9 for postherpetic neuralgia (Koopman 2009). A systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as painful diabetic neuropathy, can be more common, with prevalence rates up to 400 per 100,000-person years (McQuay 2007) illustrating how common the condition was as well as its chronicity. The prevalence of neuropathic pain was reported as being 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), as high as 8% in the UK (Torrance 2006), and about 7% in a systematic review of studies published since 2000 (Andrew 2014). Some forms of neuropathic pain, such as diabetic neuropathy and post surgical chronic pain (which is often neuropathic in origin) are increasing (Hall 2008).
Neuropathic pain is known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Conventional analgesics are usually not effective. Some patients may derive some benefit from low concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012). High concentration topical capsaicin may benefit some patients with postherpetic neuralgia (Derry 2013). Treatment is more usually by so-called unconventional analgesics such as antidepressants like duloxetine and amitriptyline (Lunn 2009; Moore 2012; Sultan 2008) or antiepileptics like gabapentin or pregabalin (Moore 2009; Moore 2011a). An overview of treatment guidelines points out some general similarities, but also differences in approach (O'Connor 2009). The proportion of patients who achieve worthwhile pain relief (typically at least 50% pain intensity reduction) is small (Moore 2013a), generally 10 to 25% more than with placebo, with numbers needed to treat to benefit (NNTs) usually between 4 and 10 (Moore 2013b).
Description of the intervention
Topical medications are applied externally and are taken up through the skin. They exert their effects close to the site of application, and there is no substantial systemic uptake or distribution. This compares with transdermal application, where the medication is applied externally and is taken up through the skin, but relies on systemic distribution for its effect.
Lidocaine is a local anaesthetic. It can be injected for dental analgesia and minor surgery, or infiltrated into wounds, but can also provide surface anaesthesia when applied topically, for example as a medicated patch, a gel, or a spray. Lidocaine is readily absorbed from mucous membranes and through damaged skin, and from injection sites, but absorption through intact skin is poor. To be clinically useful as a topical agent, lidocaine must be formulated with a carrier to facilitate transfer across the skin.
Creams, gels, foam sprays, and solutions containing lidocaine are most often used for short-term analgesia, for example before painful medical procedures or to treat cuts, burns and insect bites, but may also be used in chronic conditions. The concentrations of lidocaine in these formulations is usually around 2% to 5% w/w.
To treat chronic pain, lidocaine is usually applied as a patch (or plaster). The medicated plaster used in a common product (Versatis®) is a white hydrogel plaster containing adhesive material, which is applied to a non-woven polyethylene terephthalate backing and covered with a polyethylene terephthalate film release liner (EMC 2013). A single patch measuring 10 cm x 14 cm contains 700 mg lidocaine (5% w/w), and up to three patches can be applied daily, for up to 12 hours, leaving plaster-free periods of at least 12 hours. Plasters may be cut to size if necessary, and hair should be removed with scissors (not shaved) before application. Steady state plasma concentrations are established within four days (EMC 2013; Mick 2012).
Lidocaine is a potent antiarrhythmic drug with narrow therapeutic window, and high doses can also precipitate CNS disturbances, such as psychosis. The amount of lidocaine reaching the systemic circulation following patch use is low (of the order of 3%) and well below therapeutic antiarrythmic concentrations or toxic concentrations in individuals with good cardiac, renal, and hepatic function (Campbell 2002). Lidocaine is extensively metabolised in the liver and excreted by the kidneys. Caution is required when treating patients with severe cardiac, renal or hepatic impairment.
As with other topical applications, localised skin reactions to the plaster or carrier in the formulation may occur.
How the intervention might work
Lidocaine is a voltage-gated sodium channel inhibitor, affecting both the generation and conduction of nerve impulses. It stabilises nerve membranes, reducing ectopic activity in damaged afferent pain receptors.
Lidocaine does not cross intact skin well and when applied as a patch, with steady controlled release of the drug, the amount of lidocaine that penetrates is enough to cause analgesia, but not anaesthesia.
Why it is important to do this review
Topical lidocaine plasters have been approved as first or second line therapy for the treatment of post herpetic neuralgia in the US, Europe, UK, and many other countries, including Latin America and the Middle East. The patch and other formulations are also used off-label in clinical practice to treat other neuropathic pain conditions. It is important to review the evidence for both benefit and harm from topical lidocaine in all painful neuropathic conditions for which it is prescribed in order to make informed treatment choices.
The standards used to assess evidence in chronic pain trials have changed substantially, with particular attention being pain to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using average pain scores, or average change in pain scores, to the number of patients who have a large decrease in pain (by at least 50%); this level of pain relief has been shown to correlate with improvements in comorbid symptoms, function, and quality of life. These standards are set out in the reference guide for pain studies (Cochrane PaPaS Group 2011).
This Cochrane review will assess evidence in ways that make both statistical and clinical sense, and will use developing criteria for what constitutes reliable evidence in chronic pain (Moore 2010a). Trials included and analysed will need to meet a minimum of reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc) and size (ideally at least 500 participants in a comparison in which the NNT is four or above (Moore 1998)). This does set high standards and marks a departure from how reviews have been done previously.
Criteria for considering studies for this review
Types of studies
We will include studies if they are randomised controlled trials (RCTs) with assessment of participant outcomes following any duration of treatment, although the emphasis of the review will be on studies with eight weeks of treatment or longer. We will include only double blind studies for the review; single blind and open cohort studies will be sought for completeness and mentioned in the discussion. We require full journal publication, with the exception of online clinical trial results summaries of otherwise unpublished clinical trials and abstracts with sufficient data for analysis. We will not include short abstracts (usually meeting reports). We will exclude studies that are non-randomised, studies of experimental pain, case reports and clinical observations.
Types of participants
We will include adult participants aged 18 years and above. Participants may have one or more of a wide range of chronic neuropathic pain conditions including:
painful diabetic neuropathy;
phantom limb pain;
postoperative or traumatic neuropathic pain;
complex regional pain syndrome (CRPS) Type I and Type II;
human immunodeficiency virus (HIV) neuropathy;
spinal cord injury.
We will include studies of participants with more than one type of neuropathic pain; in such cases we will analyse results according to the primary condition. We will exclude migraine and headache studies as they are the subject of another Cochrane review (Chronicle 2004).
Types of interventions
Lidocaine at any dose, formulated for topical application, and administered for the relief of neuropathic pain and compared to placebo or any active comparator.
Types of outcome measures
We anticipate that studies will use a variety of outcome measures, with the majority of studies using standard subjective scales (numerical rating scale (NRS) or visual analogue scale (VAS)) for pain intensity or pain relief, or both. We are particularly interested in Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) definitions for moderate and substantial benefit in chronic pain studies (Dworkin 2008). These are defined as at least 30% pain relief over baseline (moderate), at least 50% pain relief over baseline (substantial), much or very much improved on the Patient Global Impression of Change (PGIC) (moderate), and very much improved on PGIC (substantial). These outcomes are different from those used in most earlier reviews using average pain scores (Khaliq 2007), concentrating as they do on dichotomous outcomes where pain responses do not follow a normal (Gaussian) distribution. People with chronic pain desire high levels of pain relief, ideally more than 50%, and with pain not worse than mild (Moore 2013a; O'Brien 2010).
We will include a 'Summary of findings' table, which will include outcomes of at least 50% and at least 30% pain intensity reduction, PGIC, adverse event withdrawals, serious adverse events and death.
Patient-reported pain relief of 30% or greater
Patient-reported pain relief of 50% or greater
PGIC much or very much improved
PGIC very much improved
Any pain-related outcome indicating some improvement
Withdrawals due to lack of efficacy
Participants experiencing any adverse event
Participants experiencing any serious adverse event, including hypersensitivity reactions, cardiac events
Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an ‘important medical event’ that may jeopardise the patient, or may require an intervention to prevent one of the above characteristics/consequences
Withdrawals due to adverse events
Specific adverse events, particularly local skin reactions
Search methods for identification of studies
We will search the following databases:
Search strategy for MEDLINE is shown in Appendix 2.
Searching other resources
We will review the bibliographies of any randomised trials identified and review articles, contact the authors and known experts in the field, and search clinical trial databases such as ClinicalTrials.gov (http://clinicaltrials.gov/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/) to identify additional published or unpublished data. We do not intend to contact investigators or study sponsors.
Data collection and analysis
The intention is to perform separate analyses according to particular neuropathic pain conditions. We will perform analyses combining different neuropathic pain conditions for exploratory purposes only.
Selection of studies
We will determine eligibility by reading the abstract of each study identified by the search. We will eliminate studies that clearly do not satisfy inclusion criteria, and we will obtain full copies of the remaining studies; decisions will be made by two review authors. Two review authors will read these studies independently and reach agreement by discussion. We will not anonymise the studies in any way before assessment. We will create a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart if appropriate (Moher 2009).
Data extraction and management
Two review authors will independently extract data using a standard data extraction form and check for agreement before entry into the Cochrane Collaboration's statistical software, Review Manager 2013, or any other analysis tool. We will include information about the pain condition and number of participants treated, drug and dosing regimen, study design (placebo or active control), study duration and follow-up, analgesic outcome measures and results, withdrawals and adverse events (participants experiencing any adverse event, or serious adverse event).
Assessment of risk of bias in included studies
We will use the Oxford Quality Score as the basis for inclusion, limiting inclusion to studies that are randomised and double-blind as a minimum (Jadad 1996).
Two authors will independently assess risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion.
We will assess the following for each study.
Random sequence generation (checking for possible selection bias). We will assess the method used to generate the allocation sequence as: low risk of bias (any truly random process, for example random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). We will exclude studies using a non-random process (for example, odd or even date of birth; hospital or clinic record number).
Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We will assess the methods as: low risk of bias (for example, telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). We will exclude studies that do not conceal allocation (for example, open list).
Blinding of outcome assessment (checking for possible detection bias). We will assess the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, for example, identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). We will exclude studies that were not double-blind.
Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). We will assess the methods used to deal with incomplete data as: low risk (< 10% of participants did not complete the study and/or used ‘baseline observation carried forward’ analysis); unclear risk of bias (used 'last observation carried forward' analysis); high risk of bias (used 'completer' analysis).
Size of study (checking for possible biases confounded by small size). We will assess studies as being at low risk of bias (≥ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (< 50 participants per treatment arm).
Measures of treatment effect
We will calculate NNTs as the reciprocal of the absolute risk reduction (ARR) (McQuay 1998). For unwanted effects, the NNT becomes the number needed to treat to harm (NNH) and is calculated in the same manner. We will use dichotomous data to calculate risk ratio (RR) with 95% CIs using a fixed-effect model unless significant statistical heterogeneity is found (Data synthesis). Continuous data will not be used in analyses.
Unit of analysis issues
The unit of randomisation will be the individual participant. The control treatment arm would be split between active treatment arms in a single study if the active treatment arms were not combined for analysis.
We will include cross-over studies and plan to use only data from the first period, if this is available. Where only combined data for both periods are reported we will treat the study as if it was a parallel study, drawing attention to the potential bias that this confers, and interpreting the results accordingly.
Dealing with missing data
We will use intention-to-treat (ITT) analysis where the ITT population consists of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post-baseline assessment. Missing participants will be assigned zero improvement.
Assessment of heterogeneity
We will deal with clinical heterogeneity by combining studies that examine similar conditions. We will assess statistical heterogeneity visually and with the use of the I2 statistic (L'Abbé 1987). When I2 is greater than 50%, we will consider possible reasons.
Assessment of reporting biases
The aim of this review is to use dichotomous data of known utility (Moore 2010c). The review does not depend on what authors of the original studies chose to report or not, though clearly difficulties will arise in studies failing to report any dichotomous results. We will extract and use continuous data, which probably poorly reflect efficacy and utility, if useful for illustrative purposes only.
We will assess publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean an NNT of 10 or higher) (Moore 2008).
We plan to use a fixed-effect model for meta-analysis. We will use a random-effects model for meta-analysis if there is significant clinical heterogeneity and it is considered appropriate to combine studies.
We plan to analyse data for each painful condition in three tiers, according to outcome and freedom from known sources of bias.
The first tier will use data meeting current best standards, where studies report the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, report an ITT analysis, last eight or more weeks, have a parallel-group design, and have at least 200 participants (preferably at least 400) in the comparison (Moore 1998; Moore 2010a; Moore 2012). These top-tier results will be reported first.
The second tier will use data from at least 200 participants but where one or more of the above conditions is not met (for example reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, or lasting four to eight weeks).
The third tier of evidence relates to data from fewer than 200 participants, or where there are expected to be significant problems because, for example, of very short duration studies of less than four weeks, where there is major heterogeneity between studies, or where there are shortcomings in allocation concealment, attrition, or incomplete outcome data. For this third tier of evidence, no data synthesis is reasonable, and may be misleading, but an indication of beneficial effects might be possible.
Subgroup analysis and investigation of heterogeneity
We plan all analyses to be according to individual painful conditions, because placebo response rates with the same outcome can vary between conditions, as can the drug-specific effects (Moore 2009).
We will carry out subgroup analysis for different topical formulations where there are sufficient data.
We will carry out sensitivity analysis for duration of study where there are sufficient data.
General institutional support is provided by the Oxford Pain Relief Trust.
Appendix 1. Methodological considerations for chronic pain
There have been changes in how efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with new criteria of what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with "any improvement". Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be longer, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. To summarise some of the recent insights that must be considered in this new review:
Pain results tend to have a U-shaped distribution rather than a bell-shaped distribution. This is true in acute pain (Moore 2011b; Moore 2011c), back pain (Moore 2010b; Moore 2014), arthritis (Moore 2010c; Moore 2014), as well as in fibromyalgia (Moore 2014; Straube 2010), and generally in chronic pain (Moore 2014); in all cases average results usually describe the experience of almost no-one in the trial. Data expressed as averages are potentially misleading, unless they can be proven to be suitable.
As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The IMMPACT group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials shorter than 12 weeks, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2010c); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic-type pain.
The proportion of patients with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis, to 30% in fibromyalgia (Moore 2009; Moore 2010c; Moore 2014; Straube 2008; Sultan 2008). A Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.
Finally, individual patient analyses and other evidence indicate that patients who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (Andrew 2014; Moore 2010d).
Appendix 2. Search strategy for MEDLINE via Ovid
(lidocaine or Lidocain or Lidocaina or Lidocainum or Lidokaiini or Lidokain or Lidokaina or Lidokainas orLignocaina or Lignocaine).mp.
1 or 2
exp Administration, Topical/
3 or 4
((pain* or discomfort*) adj10 (central or complex or myofasci* or nerv* or neuralg* or neuropath*)).mp.
((neur* or nerv*) adj6 (compress* or damag*)).mp.
randomized controlled trial.pt.
controlled clinical trial.pt.
3 and 4 and 11 and 20
Contributions of authors
Both authors wrote the protocol and will be involved in all stages of the full review.
Declarations of interest
SD and RAM have received research support from charities, government and industry at various times, but none related to this review. RAM has consulted for, and received lecture fees from, various pharmaceutical companies related to analgesics and other healthcare interventions in the last five years. None relate to this review.