This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the analgesic efficacy of nortriptyline for chronic neuropathic pain in adults, and to evaluate adverse events reported in the studies.
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
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 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 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). Many people with neuropathic pain 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).The incidence of postherpetic neuralgia in the UK appears to be increasing (Hall 2013). 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 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 post surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008).
Neuropathic pain is known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Conventional analgesics are usually not effective. Some patients may derive some benefit from a topical lidocaine patch or low-concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012; Derry 2014; Khaliq 2007). High-concentration topical capsaicin may benefit some patients with postherpetic neuralgia (Derry 2013). Treatment is more usually by so-called unconventional analgesics, such as antidepressants like duloxetine and amitriptyline (Lunn 2014; Moore 2012a; Sultan 2008), or antiepileptics such as carbamazepine, gabapentin and pregabalin (Moore 2009; Moore 2014b; Wiffen 2014). 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 2013a)) is small, generally 10% to 25% more than with placebo, with numbers needed to treat to benefit (NNTs) usually between 4 and 10 (Moore 2013b).
Chronic painful conditions comprised 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 2014a).
Description of the intervention
Nortriptyline is a tricyclic antidepressant and the main active metabolite of amitriptyline. It is not licensed in the UK or USA for treating neuropathic pain, but is commonly used for chronic pain conditions, and it is commonly used for treating neuropathic pain around the world, irrespective of licensed indications. Nortriptyline is sometimes preferred to amitriptyline because it reputedly has a lower incidence of associated adverse effects, which can increase patient compliance and can be particularly useful in older patients who are more likely to experience adverse effects such as confusion and agitation, and postural hypotension.
Nortriptyline is available as 10 mg and 25 mg tablets, and as an oral solution. When used to treat neuropathic pain, an initial dose of 10 mg daily may be gradually increased to 75 mg daily. It is usually given as a single dose at night time, to reduce any sedative effects during the day. There were over 450,000 prescriptions for nortriptyline in England in 2012, mainly for 10 mg and 25 mg tablets (PCA 2013); this compares with over 10 million prescriptions for amitriptyline in the same period. The majority of these prescriptions are likely to be for relief of depression. The main adverse effects associated with its use are due to its anticholinergic activity, and include dry mouth, weight gain, and drowsiness.
How the intervention might work
The mechanism of action of nortriptyline in the treatment of neuropathic pain remains uncertain, although it is known to inhibit both serotonin and noradrenalin reuptake. The mechanism is likely to differ from that in depression since analgesia with antidepressants is often achieved at lower dosage than the onset of any antidepressant effect; adverse events associated with its use often wane after two or three weeks, when the benefits of the drug become apparent. In addition, there is no correlation between the effect of antidepressants on mood and pain, and antidepressants produce analgesia in patients with and without depression (Onghena 1992). Nortriptyline is also known to block sodium channels, which may contribute to its analgesic effects.
Why it is important to do this review
Nortriptyline is a recommended first-line treatment for neuropathic pain (Dworkin 2010). It was included in the original review of antidepressants for neuropathic pain, but few data were identified (Saarto 2007), and that review is being split, with separate reviews for each drug. There may have been some new studies since the last review, but it is also important to re-review existing evidence using more stringent criteria for validity, including both the level of response obtained, and duration of study. The individual reviews (including amitriptyline (Moore 2012a), imipramine (Hearn 2014), and duloxetine (Lunn 2014)) will be included in an overview review of antidepressant drugs for neuropathic pain.
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 reference guide 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). 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.
To assess the analgesic efficacy of nortriptyline for chronic neuropathic pain in adults, and to evaluate adverse events reported in the studies.
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 are non-randomised, studies of experimental pain, case reports and clinical observations.
Nortriptyline is an established, and now recommended, first-line treatment for neuropathic pain, and our experience from previous reviews is that most studies will be older, small, and have methodological deficiencies according to present standards of evidence, and therefore we feel it appropriate to consider lower standards of evidence than those currently demanded for part of our analyses. This includes reviewing data from studies of shorter duration, and studies where the outcome definition is poorly defined; all studies will need to be both randomised and double-blind as a minimum. We will report the evidence available according to the current standards, and lower levels of evidence. It is important to recognise that the lower-level evidence is likely to be subject to various positive biases, and that these lower levels of evidence cannot be used to make cross-drug comparisons of efficacy with other drugs.
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 (but not limited to):
complex regional pain syndrome (CRPS) Type I;
complex regional pain syndrome (CRPS) Type II;
human immunodeficiency virus (HIV) neuropathy;
painful diabetic neuropathy (PDN);
phantom limb pain;
postherpetic neuralgia (PHN);
postoperative or traumatic neuropathic pain;
spinal cord injury;
We will include studies of participants with more than one type of neuropathic pain; in such cases we will analyse results according to the primary condition. We will exclude studies of use of nortriptyline for prevention of migraine and headache as they are the subject of another Cochrane review (Chronicle 2004).
Types of interventions
Nortriptyline 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 concentrate on dichotomous outcomes in circumstances 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 author guide. 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 CNS effects such as somnolence and dizziness.
Search methods for identification of studies
We will search the following databases:
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. 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 the 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 as the basis for inclusion, limiting inclusion to studies that are randomised and double-blind as a minimum (Jadad 1996).
Two authors will independently assess risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion.
We will assess the following for each study: random sequence generation (checking for possible selection bias). We will assess the method used to generate the allocation sequence as: low risk of bias (any truly random process, for example random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). We will exclude studies using a non-random process (for example, odd or even date of birth; hospital or clinic record number).
Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We will assess the methods as: low risk of bias (for example, telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). We will exclude studies that do not conceal allocation (for example, open list).
Blinding of outcome assessment (checking for possible detection bias). We will assess the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, for example, identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). We will exclude studies that were not double-blind.
Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). We will assess the methods used to deal with incomplete data as: low risk (< 10% of participants did not complete the study and/or used ‘baseline observation carried forward’ analysis); unclear risk of bias (used 'last observation carried forward' analysis); high risk of bias (used 'completer' analysis).
Size of study (checking for possible biases confounded by small size). We will assess studies as being at low risk of bias (≥ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (< 50 participants per treatment arm).
Measures of treatment effect
We will 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 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. Continuous data will not be used.
Unit of analysis issues
The control treatment arm will be split between active treatment arms in a single study if the active treatment arms are not combined for analysis.
If cross-over studies are included, we will use first period data only wherever possible. Where this is not reported we will analyse as if the treatment periods were parallel, but draw attention to the potential bias this may introduce.
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 and of value to patients (Moore 2010b; Moore 2013a). 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 an NNT of 10 or higher) (Moore 2008).
We plan to use a fixed-effect model for meta-analysis. We will use a random-effects model for meta-analysis if there is significant clinical heterogeneity and it is considered appropriate to combine studies.
We plan to analyse data for each painful condition in three tiers, according to outcome and freedom from known sources of bias.
The first tier will use data meeting current best standards, where studies report the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, report an intention-to-treat (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 2010a; Moore 2012b). These top-tier results will be reported first.
The second tier will use data from at least 200 participants but where one or more of the above conditions is not met (for example reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, or lasting four to eight weeks).
The third tier of evidence relates to data from fewer than 200 participants, or where there are expected to be significant problems because, for example, of very short duration studies of less than four weeks, where there is major heterogeneity between studies, or where there are shortcomings in allocation concealment, attrition, or incomplete outcome data. For this third tier of evidence, no data synthesis is reasonable, and may be misleading, but an indication of beneficial effects might be possible.
Subgroup analysis and investigation of heterogeneity
We plan all analyses to be according to individual painful conditions, because placebo response rates with the same outcome can vary between conditions, as can the drug-specific effects (Moore 2009). In the unlikely event that there are sufficient data we will carry out sensitivity analysis for dose of nortriptyline and duration of study.
We will examine details of dose escalation schedules to investigate if this could provide some basis for a sensitivity analysis, but the evidence base is known to be small.
CRG Funding Acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane PaPaS Group. Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.
Appendix 1. Methodological considerations for chronic pain
There have been changes in how efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with new criteria of what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with "any improvement". Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be longer, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. To summarise some of the recent insights that must be considered in this new review:
Pain results tend to have a U-shaped distribution rather than a bell-shaped distribution. This is true in acute pain (Moore 2011a; Moore 2011b), back pain (Moore 2010d), arthritis (Moore 2010c), 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 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; 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.
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 2010b; Moore 2014a).
Imputation methods like last observation carried forward (LOCF), used when participants withdraw from clinical trials, can overstate drug efficacy especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012b).
Appendix 2. Search strategy for MEDLINE via Ovid
exp PERIPHERAL NERVOUS SYSTEM DISEASES/
exp SOMATOSENSORY DISORDERS/
((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp.
((neur* or nerv*) adj6 (compress* or damag*)).mp.
1 or 2 or 3 or 4 or 5
(nortriptyline or Allegron or Aventyl or Noritren or Norpress or Nortrilen or Pamelor or Sensoval).mp.
7 or 8
randomized controlled trial.pt.
controlled clinical trial.pt.
6 and 9 and 18
Contributions of authors
PW, RAM, and SD wrote the protocol. RAM and SD will carry out searches, assess studies for inclusion, and extract data. PW will act as arbitrator. All authors will be involved in writing the review. RAM will be responsible for updating the review.
Declarations of interest
SD, RAM, and PW have received research support from charities, government, and industry sources at various times. RAM, DA, and PW have consulted for various pharmaceutical companies. RAM, DA, PC, and PW have received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions.