This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the analgesic efficacy of topical clonidine for chronic neuropathic pain in adults
To assess the adverse events associated with the clinical use of topical clonidine for chronic neuropathic pain
This protocol is based on a template for 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).
Description of the condition
Neuropathic pain comprises a wide range of pain condition. It is defined by the International Association of the Study of Pain as "pain caused by lesion or disease of the somatosensory nervous system" (IASP Taxonomy Working Group 2011 ; 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 (Moisset 2007). It tends to be chronic and may be present for months or years. It is complex (Apkarian 2011; Tracey 2011), and neuropathic pain features can be found in patients with joint pain (Soni 2013). Pathomechanism of neuropathic pain differs significantly from that of nociceptive pain. Nociceptive pain is a consequence of tissue damage, whereas neuropathic pain results from a dy sfunction in nervous system transmission. It was proved that changes in spinal gene expression in these two models of chronic pain are different (Rodrigues Parkitna 2006). The most characteristic clinical symptom of neuropathic pain are spontaneous pain, hyperalgesia and allodynia easily demonstrated in various animal models (Hurley 2013; Woolf 1999).
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 and/or cognitive interventions. Conventional analgesics are usually not effective. Some patients may benefit from a topical lidocaine patch or low concentration topical capsaicin, though evidence about benefits is uncertain (Anitescu 2013; Derry 2012; Khaliq 2007). High- concentration topical capsaicin may benefit some patients with post-herpetic neuralgia (Derry 2013). Treatment is more usually by so-called unconventional analgesics such as antidepressants ( e.g. duloxetine and amitriptyline) or antiepileptics (e.g. gabapentin or pregabalin) (Lunn 2009 ; Moore 2009; Moore 2011a ; Moore 2012 ; Sultan 2008). An overview of treatment guidelines points out some general similarities, but also differences in approach ( Hurley 2013; O'Connor 2009 ; Smith 2013). The proportion of patients who achieve worthwhile pain relief (typically at least 50% pain intensity reduction is small, generally 10 to 25% more than with placebo, with numbers needed to treat to benefit (NNTs) usually between 4 and 10 ( Moore 2013).
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).
Description of the intervention
Clonidine is a presynaptic alpha-2-adrenergic receptor agonist and also an agonist of imidazoline receptors (Eisenach 1996). It has been in clinical use for over 40 years. It was first registered for treatment of hypertension, however later it proved to be effective in treatment of acute and chronic pain (Neil 2011). Clonidine is an extremely potent antinociceptive agent having a potency that is equal to or greater than that reported for morphine (Gentili 1997; Samso 1996). Clonidine has been used to treat both acute and chronic pain. It may be effective when applied intravenously, epidurally and intrathecally (Asano 2000; Eisenach 1995; Hassenbusch 2002; Sierralta 1996). However, systemic and central use of clonidine is limited by undesirable adverse events including sedation, dry mouth, hypotension and rebound hypertension (Dias 1999; Puskas 2003). Recently topical forms of administration have been developed with intention to limit centrally mediated adverse events without reduction in analgesic efficacy (Sawynok 2003). Clonidine is lipophilic and easily penetrates skin to reach the local antinociceptive pathways. Half-life of clonidine is about eight hours, thus it should be applied three times daily. Clonidine in various concentrations can be prepared by compounding pharmacies (Flores 2012).
Topical clonidine proved to be an effective analgesic in several animal studies. Dogrul 2004 demonstrated that topical administration of clonidine increased pain threshold to radiant heat stimuli (measured by tail-flick test) in mice. The antinociceptive activity was limited to the part of the tail exposed to drug solution. Systemic administration of alpha-2 receptor antagonist, yohimbine, before immersion of the tail blocked the antinociceptive activity of topical clonidine (Dogrul 2004). Chi 2007 studied efficacy of topically applied clonidine in animal model of neuropathic, postoperative and inflammatory pain. Clonidine turned out to be effective in neuropathic pain, only partially effective in postoperative pain and not effective in inflammatory pain. Analgesic efficacy of clonidine in postoperative pain manifested on the sixth day of application and only reduction of thermal hyperalgesia and not mechanical allodynia was observed (Chi 2007).
How the intervention might work
The target receptors for clonidine, alpha-2 receptors, are located in the brain, spinal cord, dorsal root ganglia and on sensory neurons (Kawaski 2003; Ongioco 2000; Riedl 2009). Activation of alpha-2 receptors leads to release of an inhibitory G-protein, which down-regulates adenylate cyclase and other second messengers responsible for initiating and maintaining the abnormal excitability of nociceptors (Lavand'homme 2002). The antinociceptive effects of clonidine are mediated via spinal and supraspinal sites of action (Asano 2000; Bernard 1994; Buerkle 1998). However, it was proved in previous studies that peripheral administration of alpha-2 receptor agonists also induces antinociception (Aley 1997; Buerkle 1998; Buerkle 2000; Gentili 1996). The mechanism of action of clonidine is similar to that of opioids. Antinociceptive effects of topically administered opioids have been reported previously (Kolesnikov 1999; Kolesnikov 2000); however, tolerance to antinociceptive action was observed after repeated administration (Kolesnikov 1999). Tolerance to antinociceptive action of clonidine was also observed in animal studies and it was not attenuated by N-Methyl-D-aspartate (NMDA) receptor antagonists such as ketamine (Dogrul 2004).
Clonidine is also an imidazoline receptor agonist. Stimulation of I2-imidazoline subclass of receptors causes analgesia. I2-imidazolin receptors are located centrally in the brain and spinal cord and also peripherally on peripheral nerve endings. Activation of these peripheral imidazoline receptors may be responsible for additional mechanism of analgesic activity of topical clonidine (Khan 1999).
Why it is important to do this review
There have been attempts to use topical clonidine in the past to treat neuropathic pain; however, no clear evidence is available to support this clinical practice. Recently, new randomised clinical trials have been published on this subject. The aim of this review is to answer a question whether topical clonidine is effective in neuropathic pain and to specify in which particular neuropathic pain conditions it is effective. No Cochrane review has been done on this subject.
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 double-blind assessment of participant outcomes following two weeks of treatment or longer, although the emphasis of the review will be on studies of eight weeks or longer. We will include cross-over studies provided that there will be a clear reporting of results for the first phase. 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. There will be no language restriction.
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;
human immunodeficiency virus (HIV) neuropathy;
spinal cord injury.
Types of interventions
Topical clonidine is administered to a painful area for the relief of neuropathic pain in a form of cream, ointment, gel, patch or plaster and compared to placebo or any active comparator. We will include studies where active comparator is administered via any route : topically, orally, intravenously, subcutaneously, etc. We will not include studies where transdermal application of clonidine is used with intention to produce systemic effect, not a local effect.
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, 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 (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. 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 somnolence and dizziness
Skin biopsy results
Search methods for identification of studies
We will search the following databases:
We will use medical subject headings (MeSH) or equivalent and text word terms. There will be no language restrictions. Searches will be tailored to individual databases. The search strategy for MEDLINE is shown in Appendix 2.
Searching other resources
We will search the metaRegister of controlled trials (mRCT) (http://www.controlled-trials.com/mrct/ ), ClinicalT rials.gov (http://clinicaltrials.gov/ ) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/) for ongoing trials. In addition, reference lists of reviews and retrieved articles will be checked for additional studies and citation searches will be performed on key articles. Experts in the field will be contacted for unpublished and ongoing trials. We will not 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 (A. Wrzosek. J. Woron). We will obtain full texts of studies identified by at least one author. Two authors (A.Wrzosek, J. Woron) will independently read the full texts of these studies and decide whether they meet inclusion criteria. In case of disagreement conclusion will be reached by discussion or, if not possible, opinion of third author ( J. Wordliczek or J. Dobrogowski) will solve the disagreement. 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 diagram in the full review to document the screening process ( Liberati 2009 ), as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Data extraction and management
Two review authors (A. Wrzosek, J. Woron) will independently extract data from the studies using a standard data extraction form (Appendix 3). Any disagreement will by resolved by consultation and discussion with a third author (J. Wordliczek or J. Dobrogowski). One author will enter data into the Cochrane Collaboration's statistical software, Review Manager 2013, and another author will check it for correctness. We will include the following data:
number of participants screened/enrolled/randomised to each treatment arm;
number of males;
duration of pain condition;
mean baseline pain intensity;
intervention: form of application, place of application, concentration, dose, dosing regimen;
control: form of application, place of application, concentration, dose, dosing regimen;
other important information.
Assessment of risk of bias in included studies
We will use the Oxford Quality Score as the basis for inclusion ( Jadad 1996), limiting inclusion to studies that are randomised and double-blind as a minimum.
Two authors (A. Wrzosek, J. Wordliczek) 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 ratios (RRs) 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 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 only if clear reporting for the first cross-over phase is available.
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 two 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 the l ast observation carried forward (LOCF) or other imputation method for dropouts, report an ITT analysis, last 8 to 12 weeks or longer, have a parallel-group design, and where there are at least 200 participants (preferably at least 400) in the comparison. These top-tier results will be reported first.
The second tier will use any available data, but where one or more of these conditions are not met, for example reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, lasting 2 to 8 weeks, and where the numbers of participants and studies are small
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). However, there is a high probability that there will be to few data for any meaningful subgroup analysis.
We do not plan to conduct any sensitivity analyse s because the evidence base is known to be too small to allow reliable analysis; results from neuropathic pain of different origins will not be pooled in the primary analyses. We will examine details of different concentrations of drug in the unlikely situation that this could provide some basis for a sensitivity analysis.
Appendix 1. Methodological considerations for chronic pain
There have been several recent 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 2010c), arthritis (Moore 2010b), as well as in fibromyalgia (Straube 2010); 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 2009 ); 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 2010b; 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, presently unpublished individual patient analyses 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 (Moore 2010d).
Appendix 2. MEDLINE (Ovid) s earch strategy
exp PERIPHERAL NERVOUS SYSTEM DISEASES/
exp SOMATOSENSORY DISORDERS/
((pain* or discomfort*) adj10 (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)).mp.
((neur* or nerv*) adj6 (compress* or damag*)).mp.
1 or 2 or 3 or 4 or 5
(Clonidine or clofelin or klofelin or m5041t or catapres* or clopheline or m-5041t or st-155 or klofenil or isoglaucon or clofenil or hemiton or st155 or catapresan or chlophazolin or gemiton or dixarit).mp
7 or 8
6 and 9
randomized controlled trial.pt.
controlled clinical trial.pl
exp animals/ not humans.sh.
19 not 20
21 and 10
Appendix 3. Data extraction form
Number of patients screened/enrolled:
Number of randomised patients (C/P):
Number of patients who received allocated intervention (C/P):
Mean age (C/P):
Number of males (C/P):
Duration of pain condition (years ± SD; C/P):
Mean baseline pain intensity (NPRS; mean ± SD; C/P):
C - clonidine group; P - placebo group
Risk of bias assessment
|Domain||Risk of bias|
Support for judgement
|Low risk||High risk||Unclear|
Random sequence generation
| || || || |
| || || || |
Blinding of participants and personnel
| || || |
Outcome group: All/
| (if required)|| || || |
Blinding of outcome assessment
| || || |
Outcome group: All/
| (if required)|| || || |
Incomplete outcome data
| || || || |
Selective outcome reporting?
| || || || |
|Other bias|| || || || |
Contributions of authors
A. Wrzosek, J. Wordliczek and J. Dobrogowski wrote the protocol. A. Wrzosek and J. Woron will carry out searches, assess studies for inclusion and extract data. J. Wordliczek and J. Dobrogowski will solve any discrepancies. All authors will be involved in writing the review. All authors will be responsible for updating the review.