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; Moore 2012a; Appendix 1).
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). Neuropathic pain is featured by pain sensations of unpleasant character (e.g. 'shooting' or 'burning' pains) that is spontaneous or evoked by pinprick, vibration, hot or cold pressure, or simple touch that does not normally provoke pain. Also, neuropathic pain is characterised by altered sensation and numbness in the area of pain.
Neuropathic pain tends to be chronic and may be present for months or years. 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). 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. 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 with neuropathic pain 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 for neuropathic pain is more usually by so-called unconventional analgesics such as antidepressants like duloxetine and amitriptyline (Lunn 2009; Moore 2012b; Sultan 2008), or antiepileptics like gabapentin or pregabalin (Moore 2009a; Moore 2011a). An overview of treatment guidelines for neuropathic pain 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 2013b), generally 10 to 25% more than with placebo, with the number needed to treat for an additional beneficial outcome (NNT) 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). A US study found the healthcare costs were 3-fold higher for people with neuropathic pain than matched control subjects (Berger 2004). A UK study and a German study showed a 2- to 3-fold higher level of use of healthcare services in people with neuropathic pain than those without (Berger 2002; Berger 2009).
Description of the intervention
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesics in general (Laine 2001). NSAIDs act by inhibiting the cyclooxygenases (COXs), which synthesise prostaglandins that are involved in inflammation and pain. The analgesic and anti-inflammatory actions of NSAIDs are attributed to the inhibition of cyclooxygenase-2 (COX-2), while their adverse gastrointestinal effects are attributed to the inhibition of cyclooxygenase-1 (COX-1). Traditional NSAIDs such as ibuprofen are non-selective. COX-2-selective NSAIDs were thus developed to reduce the adverse gastrointestinal effects, but were later found to increase the risk of myocardial infarction and stroke. Therefore, rofecoxib and valdecoxib have been withdrawn from the market. However, some traditional NSAIDs with relative selectivity for COX-2 were also found to increase the risk of myocardial infarction (Grosser 2011).
How the intervention might work
Damage of the peripheral nerves is followed by an inflammatory reaction that relates to increased production of prostaglandins, which amplifies sodium currents and calcium influx in peripheral nociceptive neurons and enhances neurotransmitter release in the CNS and depolarisation of second-order nociceptive neurons (Vo 2009). NSAIDs inhibit the production of prostaglandins, and thus could lessen the peripheral and central sensory hypersensitivity that occurs with nerve injury-associated inflammation. NSAIDs have been shown to reduce sensory hypersensitivity in animal models (Hasnie 2007; Kawakami 2002).
Why it is important to do this review
Although often considered lacking adequate evidence, NSAIDs are widely used in the management of neuropathic pain (Di Franco 2010; Vo 2009). Previous surveys found 18-47% of affected people reported using NSAIDs specifically for their neuropathic pain (Vo 2009). Therefore, it is desirable to assess the best evidence on the efficacy and safety of NSAIDs in managing neuropathic pain. In chronic pain generally, and neuropathic pain in particular, few drugs produce good pain relief that patients want in more than a minority of patients (Moore 2013c), which makes proper review of efficacy and harm important. This review will assist policy makers, physicians, and consumers in making decisions regarding the use of NSAIDs in managing neuropathic pain.
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.
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 2010a; Moore 1998). This sets high standards and marks a departure from how systematic reviews have been done previously.These standards have been set out in the authors' reference guide for the Cochrane Pain, Palliative, and Supportive Care Review Group (Cochrane PaPaS Group 2012). This Cochrane systematic review will use the standards to assess evidence and take both statistical and clinical significance into consideration, in order to provide an overview of the analgesic efficacy and safety of NSAIDs in neuropathic pain.
- To assess the analgesic efficacy of oral NSAIDs for chronic neuropathic pain in adults when compared to placebo or another active intervention
- To assess the adverse events associated with the clinical use of oral NSAIDs 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, 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;
- postherpetic neuralgia;
- trigeminal neuralgia;
- phantom limb pain;
- postoperative or traumatic neuropathic pain;
- cancer-related neuropathy;
- human immunodeficiency virus (HIV) neuropathy;
- spinal cord injury; or
- complex regional pain syndrome Type I.
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.
Types of interventions
NSAIDs at any dose, by any route, administered for the relief of neuropathic pain and compared to placebo or any active comparator (for example another NSAID).
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 (Seidel 2013), 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). The time point of outcome measures will be week 12, which is considered a standard measurement point and typically required by regulatory bodies (Moore 2010a). However, trials that report outcomes at different time points will be included.
We will include a 'Summary of findings' table as set out in the author guide (Cochrane PaPaS Group 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.
- 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
Search methods for identification of studies
We will search the following databases:
- Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library;
- MEDLINE (via Ovid);
- EMBASE (via Ovid);
Search strategy for MEDLINE is 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 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.
Data collection and analysis
We will produce a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart (Liberati 2009).
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. Two review authors (SW, LK) will read these studies independently and reach agreement by discussion. We will not anonymise the studies in any way before assessment.
Data extraction and management
Two review authors (SW, LK) will independently extract data using a standard form and check for agreement before entry into the Cochrane Collaboration's statistical software, Review Manager 2013, or any other analytical 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 (SW, LK) 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, e.g. random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). Studies using a non-random process (e.g. odd or even date of birth; hospital or clinic record number) will be excluded.
- 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 (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). Studies that do not conceal allocation (e.g. open list) will be excluded.
- 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, e.g. 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). Studies that were not double-blind will be excluded.
- 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 the NNT 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 (Assessment of heterogeneity). 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. Cross-over study designs will use only data from the first treatment phase, if presented in that way.
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 assess clinical heterogeneity inherent in the study design, participants, interventions, and outcome measures to determine whether a meta-analysis that combines studies that examine similar conditions is appropriate. The anticipated clinical heterogeneity includes various dosages of the same NSAID and various time points of outcome measurement. We will assess statistical heterogeneity visually and with the use of the I
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 analyse according to individual painful conditions, because placebo response rates with the same outcome can vary between conditions, as can the drug-specific effects (Moore 2009a). We will use a fixed-effect model for meta-analysis; a random-effects model will be used 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 last 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 four to eight weeks, and where the numbers of participants and studies are small.
Subgroup analysis and investigation of heterogeneity
When sufficient trials are available, we will conduct subgroup analyses to investigate heterogeneity according to:
- different dosages of NSAIDs;
- different time points of outcome measurement.
When sufficient trials are available, we will conduct a sensitivity analysis by excluding studies with high risk of bias. We will identify high risk of bias as one or more domains on the risk of bias tool judged as 'high risk' as per the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will categorise all remaining trials as low risk of bias for this analysis.
We acknowledge the contribution of Dr Shu-Hui Wang and Dr Liang Tseng Kuo to previous versions of this protocol.
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.
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 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 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 2009b); 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 2009a; 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 2009a). 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. Search strategy for MEDLINE via Ovid
2. (nerve adj1 pain$).tw.
4. (neuropathic adj1 pain).tw.
5. 1 or 2 or 3 or 4
6. exp Anti-Inflammatory Agents, Non-Steroidal/
8. "non-steroidal anti-inflammatory drug$".tw.
19. diclofenac sodium.tw.
33. Mefenamic Acid/
34. Mefenamic Acid.tw.
44. tiaprofenic acid.tw.
46. 5 and 45
47. randomized controlled trial.pt.
48. controlled clinical trial.pt.
51. drug therapy.fs.
55. 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54
56. exp animals/ not humans.sh.
57. 55 not 56
58. 46 and 57
Protocol first published: Issue 12, 2013
Contributions of authors
CCC and RAM wrote the protocol. CCC and SHW will carry out searches with the assistance of the Editorial Base. SHW, KLT, and CCC will identify studies for inclusion, and extract data. SHW and CCC will enter data into RevMan, analysis of data, and write the review draft. All authors will be involved in writing the full review.
Declarations of interest
Sources of support
- Chang Gung Memorial Hospital, Chiayi, Taiwan.
- No sources of support supplied
At 13 April 2015, the title was amended from 'Nonsteroidal anti-inflammatory drugs for neuropathic pain' to 'Oral nonsteroidal anti-inflammatory drugs for neuropathic pain' after discussion with the editors and authors. Dr Phil Wiffen and Dr Sheena Derry joined the author team.