This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the analgesic efficacy of topiramate for chronic neuropathic pain and fibromyalgia.
To assess the adverse events associated with the clinical use of topiramate for chronic neuropathic pain and fibromyalgia.
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). Moreover, neuropathic pain and fibromyalgia patients experience similar sensory phenomena (Koroschetz 2011).
Neuropathic pain tends to be chronic and may be present for months or years. Fibromyalgia is defined as widespread pain for longer than three months with pain on palpation at 11 or more of 18 specified tender points (Wolfe 1990), and is frequently associated with other symptoms such as poor sleep, fatigue, and depression. More recently, a definition of fibromyalgia has been proposed based on symptom severity and the presence of widespread pain (Wolfe 2010). The cause, or causes, are not well understood, but it has features in common with neuropathic pain, including changes in the CNS. Many people with these conditions are significantly disabled with moderate or severe pain for many years.
In primary care in the UK the incidences, per 100,000 person years observation, have been reported as 28 (95% 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 (Moore 2013a). Some forms of neuropathic pain, such as diabetic neuropathy and post surgical chronic pain (which is often neuropathic in origin) are increasing (Hall 2008). Fibromyalgia is common, especially in women, with an all-age prevalence of 12%, and a female to male ratio of 6:1 (McNally 2006).
Neuropathic pain and fibromyalgia are 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 derive some benefit from a topical lidocaine patch or low concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012; Khaliq 2007). High concentration topical lidocaine 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 2012a; Sultan 2008) or antiepileptics like gabapentin or pregabalin (Moore 2009; Moore 2011). 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 (Moore 2013b)) is small, generally 10 to 25% more than with placebo, with NNTs usually between 4 and 10.
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 (Moore 2013a).
Description of the intervention
Topiramate is a weak inhibitor of carbonic anhydrase isoenzymes (Kanda 1996). Therefore, it is associated with carbonic anhydrase-related adverse effects such as nephrolithiasis, metabolic acidosis and potentially a compensatory hyperventilating respiratory alkalosis, and perioral or digital paraesthesias. Other well recognised adverse effects of topiramate include somnolence (sleepiness), dizziness, fatigue, nausea, poor concentration and weight loss (Chong 2003; Walia 2004). Topiramate is associated with weight loss (Antel 2012), and there are reports of reversible anorgasmia in men and women (Sun 2006). Topiramate does not appear to be associated with oral cleft or major congenital malformations in the newborn when taken by women during pregnancy (Green 2012).
Topiramate is licensed for the treatment of epilepsy and as a prophylaxis for migraine in the UK and USA. These indications have been the subjects of separate Cochrane reviews (Chronicle 2004; Jette 2002). Topiramate is taken orally, and is available as 25 mg, 50 mg, 100 mg, and 200 mg tablets, and 15 mg, 25 mg and 50 mg sprinkle capsules. It is marketed under the trade name Topamax®, and generic formulations are available. The dose is usually titrated slowly, to minimise adverse effects, until a therapeutic response is achieved, or tolerability reached.
How the intervention might work
Topiramate has multiple modes of action, some of which are thought to be useful in the treatment of neuropathic pain. Topiramate has been shown to block activity-dependent, voltage-gated sodium channels, enhance the action of ɣ-aminobutyric acid (GABA)-A receptors, inhibit L-type voltage-gated calcium channels, pre-synaptically reduce glutamate release and post-synaptically block kainate/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Chong 2003) all of which have been reported to be involved in the genesis or control of neuropathic pain.
Why it is important to do this review
Topiramate has been used to treat various neuropathic pain conditions, using various study designs, with conflicting results. It is important to review all the evidence to determine its place in the treatment of neuropathic pain and fibromyalgia.
The original review of antiepileptic drugs for neuropathic pain has been withdrawn (Wiffen 2010, originally published in 2005), and split into reviews for individual drugs, including carbamazepine (Wiffen 2011a), lamotrigine (Wiffen 2011b), gabapentin (Moore 2011a), pregabalin (Moore 2009), valproic acid (Gill 2011), phenytoin (Birse 2012), and clonazepam (Corrigan 2012). These separate reviews for individual drugs use more stringent criteria of validity, which include the level of response obtained, the duration of study and method of imputation of missing data (Moore 2012a). Appendix 1 gives details of recent changes to the thinking about chronic pain and evidence.
This Cochrane review will therefore 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 minimum criteria for reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc) and size (ideally at least 200 participants in each treatment arm in a comparison in which the number needed to treat for an additional beneficial outcome (NNTB) is four or above (Moore 1998)). This does set high standards and marks a departure from how reviews have been done previously.
This review will be one of a series, and will be included in an overview of antiepileptic drugs for neuropathic pain and fibromyalgia.
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, though the emphasis of the review will be on studies of eight weeks or longer. 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
Studies should 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;
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.
Migraine and headache studies will be excluded as they are the subject of another Cochrane review (Chronicle 2004).
Types of interventions
Oral topiramate, at any dose, administered for the relief of neuropathic pain or fibromyalgia 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 Patient Global Impression of Change (PGIC) (moderate), and very much improved on PGIC (substantial). These outcomes are different from those set out in the earlier review (Wiffen 2010), 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 as set out in the Cochrane Pain, Palliative and Supportive Care Group author guide (AUREF 2012). The 'Summary of findings' table will include outcomes of at least 30% and at least 50% 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.
Weight loss or weight change.
These outcomes are not eligibility criteria for this review, but are outcomes of interest within whichever studies are included.
Search methods for identification of studies
The following databases will be searched:
The search strategy for MEDLINE is in Appendix 2.
Searching other resources
We will review the bibliographies of any randomized trials identified and review articles, and search clinical trial databases (for example, ClinicalTrials.gov (ClinicalTrials.gov) and WHO ICTTRP (http://apps.who.int/trialsearch/) to identify additional published or unpublished data. 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, or fibromyalgia. Analyses combining different neuropathic pain conditions will be done 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 PRISMA flow chart if appropriate.
Data extraction and management
Two review authors will independently extract data using a standard form and check for agreement before entry into RevMan (RevMan 2012) 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 (Jadad 1996) as the basis for inclusion, limiting inclusion to studies that are randomised and double-blind as a minimum.
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 NNTBs as the reciprocal of the absolute risk reduction (ARR) (McQuay 1998). For unwanted effects, the NNTB becomes the number needed to treat for an additional harmful outcome (NNTH) and is calculated in the same manner. We will use dichotomous data to calculate risk ratio (RR) with 95% confidence intervals (CI) using a fixed-effect model unless significant statistical heterogeneity is found (see below). We will not use continuous data 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.
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 (L'Abbé 1987) and with the use of the I² statistic. 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 2010b). 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 used 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 last observation carried forward (LOCF) or other imputation method for dropouts, report an ITT analysis, last eight 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 four to eight 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). We do not plan subgroup analyses since experience of previous reviews indicates that there will be too few data for any meaningful subgroup analysis.
We plan no sensitivity analysis 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 dose escalation schedules in the unlikely situation that this could provide some basis for a sensitivity analysis.
Dr Sivakumar Sathasivam and Prof Turo Nurmikko, authors of the first published version of this protocol.
The editorial base of the Cochrane Neuromuscular Disease Group is supported by the MRC Centre for Neuromuscular Diseases.
Appendix 1. Methodological considerations in 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 bimodal rather than a normal distribution; the majority of patients have either very poor pain relief or very good pain relief. This is true in acute pain (Moore 2011b; Moore 2011c), back pain (Moore 2010c), arthritis (Moore 2010d), as well as in neuropathic pain (Moore 2012b) and fibromyalgia (Straube 2010); in all cases mean 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 Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (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 2010b); 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, a presently unpublished review summarises data 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 2013a).
Appendix 2. MEDLINE (OvidSP) search strategy
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
5 drug therapy.fs.
10 exp animals/ not humans.sh.
11 9 not 10
12 (topiramate or Topamax).mp.
13 exp Pain/
15 (pain$ or fibromyalgi$ or neuralgi$ or analgesi$ or discomfort$).mp.
17 11 and 12 and 16
18 remove duplicates from 17
Contributions of authors
All authors were involved in writing the protocol.
Declarations of interest
SD and PW have received research support from charities, government and industry sources at various times, but none relate to this review.
RAM has consulted for various pharmaceutical companies and received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions, including (in the past five years) AstraZeneca, Eli Lilly, Flynn Pharma, Furtura Medical, Grünenthal, GSK, Horizon Pharma, Lundbeck, Menarini, MSD, Pfizer, Reckitt Benckiser, Sanofi aventis, Urgo, Astellas, and Vifor Pharma.
MPL has received honoraria for consultation from Baxter Pharmaceuticals, CSL Behring and LfB and a travel support grant from Grifols. He has no interests to declare related to this review.