This review 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). An overview review of antiepileptic drugs for treating neuropathic pain found no Cochrane review for zonisamide (Wiffen 2013).
Description of the condition
The 2011 International Association for the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011) based on a definition agreed at 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). The genesis of neuropathic pain is complex (Apkarian 2011; Baron 2010; Baron 2012; Tracey 2011; von Hehn 2012), and neuropathic pain features can be found in patients with joint pain (Soni 2013). Many people with neuropathic pain conditions are disabled with significant levels of pain for many years. Chronic painful conditions comprise 5 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 2014a).
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), about 7% in a systematic review of studies published since 2000 (Moore 2014a), and 7% to 10% in a systematic review of epidemiological studies published between 1966 and 2012 (van Hecke 2014). The prevalence of some types of neuropathic pain, such as diabetic neuropathy and postsurgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008). Estimates vary between studies, often because of small numbers of cases. 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.
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 (facial pain), 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). In other studies the incidence of trigeminal neuralgia has been estimated at 4 in 100,000 per year (Katusic 1991; Rappaport 1994), while 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).
Neuropathic pain is difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention (Moore 2013b). 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 a topical lidocaine patch or low concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012; Khaliq 2007). High concentration topical capsaicin may benefit some patients with postherpetic neuralgia (Derry 2013). Treatment is often by so-called unconventional analgesics, such as antidepressants like duloxetine and amitriptyline (Lunn 2014; Moore 2012a; Moore 2014b) or antiepileptics like gabapentin or pregabalin (Moore 2009; Moore 2011a). While treatment guidelines have general similarities based on the evidence available, they are not always consistent with one another (O'Connor 2009). The proportion of patients who achieve worthwhile, meaningful pain relief (typically at least 50% pain intensity reduction (Moore 2013a)) is small, generally 10% to 25% more than with placebo, with numbers needed to treat (NNT) to benefit usually between 4 and 10 (Moore 2013b).
Description of the intervention
Zonisamide is a sulphonamide antiepileptic drug created in the 1970s and found to have potent anticonvulsant activity. It is approved in the USA, UK, Japan, and Australia for treatment of various forms of epilepsy. Daily doses of oral zonisamide are usually in the range of 200 mg to 600 mg daily. Typical adverse events in zonisamide studies in epilepsy include somnolence, dizziness, and anorexia.
How the intervention might work
Zonisamide probably has a range of different modes of action. These include reducing sodium-dependent high firing action potentials in nerves, and inhibiting some calcium currents that may prevent the spread of seizure discharges between cells. Zonisamide also alters dopamine, 5-HT, and acetylcholine metabolism, and weakly inhibits carbonic anhydrase, as well as having effects on GABA-mediates neuronal inhibition and glutamate release (Brodie 2012). Any or all of these effects could possibly have relevance to treatment of neuropathic pain, either peripherally or centrally. Animal studies (Bektas 2014; Sakaue 2004; Tanabe 2008) and human studies in central (Takahashi 2004) and peripheral (Atli 2005; Krusz 2003) neuropathic pain exist with positive outcomes.
Why it is important to do this review
Zonisamide is not commonly prescribed for neuropathic pain and it is not licensed for the treatment of neuropathic pain in the UK or USA, but the potential for benefit from this drug needs to be investigated. This review is one of a series of reviews covering the role of antiepileptics in neuropathic pain, and this review will be included in an update of an overview review (Wiffen 2013).
The standards used to assess evidence in chronic pain trials have changed substantially, with particular attention being paid 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 Cochrane Pain, Palliative and Supportive Care Group's Author and Referee Guidance for pain studies (AUREF 2012).
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; Moore 2012b). Studies 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 400 participants in a comparison in which the NNT is four or above (Moore 1998)). This sets high standards and marks a departure from how reviews have been done previously.
To assess the analgesic efficacy and associated adverse events of zonisamide for chronic neuropathic pain in adults.
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 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 were non-randomised, studies of experimental pain, case reports and clinical observations.
Types of participants
Studies will include adults aged 18 years and above. Participants may have one or more of a wide range of chronic neuropathic pain conditions, but we will specifically search for and include:
- painful diabetic neuropathy;
- postherpetic neuralgia;
- trigeminal neuralgia;
- phantom limb pain;
- postoperative or traumatic neuropathic pain;
- complex regional pain syndrome (CRPS), Type I and Type II;
- cancer-related neuropathy;
- human immunodeficiency virus (HIV) neuropathy;
- spinal cord injury; and
- poststroke pain.
If studies included participants with more than one type of neuropathic pain, we plan to analyse results according to the primary condition.
Types of interventions
Zonisamide at any dose, by any route, 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 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 (Moore 2013a; O'Brien 2010).
We will include a 'Summary of findings' table as set out in the author guide (AUREF 2012). The 'Summary of findings' table will include outcomes of at least 50% and at least 30% pain intensity reduction, PGIC, adverse event withdrawals, serious adverse events and death.
- Participant-reported pain relief of 30% or greater.
- Participant-reported pain relief of 50% or greater.
- PGIC much or very much improved.
- PGIC very much improved.
- Any pain-related outcome indicating some improvement.
- 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.
- Specific adverse events, particularly somnolence and dizziness.
- Withdrawals due to adverse events.
- Withdrawals due to lack of efficacy.
Search methods for identification of studies
We will search the following databases without language restrictions.
- The Cochrane Central Register of Controlled Trials (CENTRAL) (via the Cochrane Library);
- MEDLINE (via Ovid); and
- EMBASE (via Ovid).
The search strategy for MEDLINE is in Appendix 2.
Searching other resources
We will review bibliographies of any RCTs we identify, and review articles, and search two clinical trial databases (ClinicalTrials.gov (ClinicalTrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (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. Analyses combining different neuropathic pain conditions, if done, would be for exploratory purposes only.
Selection of studies
Two review authors will independently determine eligibility by reading the abstract of each study identified by the search. Independent review authors will eliminate studies that clearly do not satisfy inclusion criteria, and obtain full copies of the remaining studies. Two review authors will read these studies independently to select relevant studies, and in the event of disagreement, a third author will adjudicate. We will not anonymise the studies in any way before assessment. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart will show the status of identified studies.
Data extraction and management
Two review authors will independently extract data using a standard form and check for agreement before entry into Review Manager (RevMan 2012). 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 (PW and SD) 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); or 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); or 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); or 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, or used ‘baseline observation carried forward’ analysis, or both); unclear risk of bias (used 'last observation carried forward' analysis); or 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); or 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 (see below). We will not use continuous data in analyses.
Unit of analysis issues
For cross-over studies, we plan to use first period data only, wherever possible.
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 postbaseline assessment. We will assign missing participants zero improvement, wherever possible.
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 the review is to use dichotomous data of known utility (Moore 2010d). The review will 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 a 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 we consider it appropriate to combine studies.
We plan to analyse efficacy 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 2012a). These top-tier results would be reported first.
- The second tier will use data from at least 200 participants, but where one or more of the above conditions are 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 will use data from studies including 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
If data allow, 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 plan no sensitivity analysis because the evidence base is known to be too small to allow reliable analysis. We will examine details of dose escalation schedules in the unlikely situation that this could provide some basis for a sensitivity analysis.
Institutional support is provided by the Oxford Pain Relief Trust. The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pain, Palliative and Supportive Care Review Group. Disclaimer: The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the NIHR, National Health Service (NHS) or the Department of Health.
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, the following are 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 2010e), arthritis (Moore 2010c), as well as in fibromyalgia (Straube 2010), and generally in chronic pain (Moore 2014b); 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 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 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 2014b; Straube 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 reasons for doing so.
Appendix 2. Search strategy for MEDLINE via OVID
- (zonisamid* or Exceglan or Excegram or Excegran or Zonegran).mp.
- exp Pain/
- (pain* or analges*).mp.
- 2 or 3
- 1 and 4
Contributions of authors
Protocol: RAM and SD wrote the protocol, based on a Cochrane Pain, Palliative and Supportive Care (PaPaS) Group template for antiepileptic drugs for neuropathic pain. All authors approved it.
Review: RAM and SD will search for studies, select studies for inclusion, and carry out data extraction. PW and ML will act as arbitrators. All authors will be involved in writing the review.
Declarations of interest
No author has any interests to declare related to this review.
For transparency we declare that we have received research support from charities, government and industry sources at various times, but none relate to this review.
We are funded by the NIHR for work on a series of reviews informing the unmet need of chronic pain and providing the evidence for treatments of pain.
Sources of support
- Oxford Pain Relief Trust, UK.General institutional support
- The National Institute for Health Research (NIHR), UK, UK.NIHR Cochrane Programme Grant: 13/89/29 - Addressing the unmet need of chronic pain: providing the evidence for treatments of pain.