Antidepressant drugs for neuropathic pain ‐ an overview of Cochrane reviews

Abstract

This is a protocol for a Cochrane Review (Overview). The objectives are as follows:

To provide an overview of the relative analgesic efficacy of antidepressants compared with placebo or other active treatments in neuropathic pain, and to report on adverse events associated with their use.

Background

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), and based on a definition agreed at an earlier consensus meeting (Treede 2008). Neuropathic pain is caused by injury to the nervous tissue, either peripheral or central and it can be followed by plastic changes in the central nervous system (Moisset 2007). The origin of neuropathic pain is complex (Baron 2010; Baron 2012; Tracey 2011; von Hehn 2012), and neuropathic pain features can be found in people with joint pain (Soni 2013).

Many people with neuropathic pain conditions are significantly disabled with moderate or severe pain for many years. Chronic pain 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 healthcare costs (Moore 2014a).

Neuropathic pain is usually divided according to the cause of nerve injury. There may be many causes, but some common causes of neuropathic pain include diabetes (painful diabetic neuropathy, PDN), shingles (postherpetic neuralgia, PHN), amputation (stump and phantom limb pain), neuropathic pain after surgery or trauma, stroke or spinal cord injury, trigeminal neuralgia, and human immunodeficiency virus (HIV) infection. Sometimes the cause is not known.

In systematic reviews, the overall prevalence of neuropathic pain in the general population is reported to be between 7% and 10% (van Hecke 2014), and about 7% in a systematic review of studies published since 2000 (Moore 2014a). In individual countries, prevalence rates have been reported as 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), and up to 8% in the UK (Torrance 2006). Some forms of neuropathic pain, such as PDN and post‐surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008). In the future, the incidence of PHN may decrease if vaccination programmes are introduced; for example, vaccination for herpes zoster is ongoing in the UK.

Estimates of incidence vary between individual studies for particular origins of neuropathic pain, often because of small numbers of cases. In primary care in the UK, between 2002 and 2005, the incidences (per 100,000 person‐years' observation) were 28 (95% confidence interval (CI) 27 to 30) for PHN, 27 (26 to 29) for trigeminal neuralgia, 0.8 (0.6 to 1.1) for phantom limb pain and 21 (20 to 22) for PDN (Hall 2008). Others have estimated an incidence of 4 in 100,000 per year for trigeminal neuralgia (Katusic 1991; Rappaport 1994), and of 12.6 per 100,000 person‐years for trigeminal neuralgia and 3.9 per 100,000 person‐years for PHN in a study of facial pain in the Netherlands (Koopman 2009). One systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as PDN, can be more common than other neuropathic pain conditions, with prevalence rates up to 400 per 100,000 person‐years (McQuay 2007).

Neuropathic pain is difficult to treat effectively, with only a minority of people experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, combining pharmacological interventions with physical or cognitive (or both) interventions. Conventional analgesics such as paracetamol and nonsteroidal anti‐inflammatory drugs are not thought to be effective, but are frequently used (Di Franco 2010; Hall 2013; Vo 2009). Some people may derive some benefit from a topical lidocaine patch or low‐concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012; Derry 2014). High‐concentration topical capsaicin may benefit some people with PHN (Derry 2013). Treatment is often by so‐called 'unconventional analgesics', such as antidepressants (duloxetine and amitriptyline; Lunn 2014; Moore 2012a; Sultan 2008), or antiepileptics (gabapentin or pregabalin; Moore 2009; Moore 2014b; Wiffen 2013).

The proportion of people who achieve worthwhile pain relief (typically at least 50% pain intensity reduction; Moore 2013a) is small, generally only 10% to 25% more than with placebo, with numbers needed to treat for an additional beneficial outcome (NNT) usually between 4 and 10 (Kalso 2013; Moore 2013b). Neuropathic pain is not particularly different from other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment (Moore 2013b).

One overview of treatment guidelines pointed out some general similarities between recommendations, but guidelines are not always consistent with one another (O'Connor 2009), nor followed (Hall 2013). The current National Institute for Health and Care Excellence (NICE) guidance in the UK suggests offering a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain (with the exception of trigeminal neuralgia), with switching if first, second, or third drugs tried are not effective or not tolerated (NICE 2013). Antidepressant drugs are also suggested as first‐line agents in new Canadian guidelines (Moulin 2014), and in updated guidance from the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (Finnerup 2015).

Description of the interventions

Certain antidepressants suppress pain, and have been used in pain management since the 1970s (Walsh 1983; Watson 1982). The clinical impression from extended use over many years is that antidepressants are useful for some neuropathic pain symptoms, and that effects on pain relief are divorced and different from effects on depression; for example, the effects of tricyclic antidepressants (TCAs) on pain may occur at different, often lower, doses than those on depression. Amitriptyline is one of the most commonly used drugs for treating neuropathic pain in the UK (Hall 2013).

Antidepressant drugs are classified in several different types, including:

1. tricyclic antidepressants (TCA): amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, maprotiline, plus others;

2. serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRI): duloxetine, venlafaxine, milnacipran;

3. selective serotonin reuptake inhibitors (SSRI): fluoxetine, paroxetine, citalopram;

4. dopamine noradrenaline reuptake inhibitors (DNRI): bupropion.

How the intervention might work

Pain that manifests in different diseases may operate through common mechanisms, but the same symptom in two people may be caused by different mechanisms. Therefore, it is difficult to predict the mechanisms responsible for an individual's pain based on the aetiology of the neuropathy or on the distribution or nature of symptoms (Woolf 1999).

Pain pathways are complicated, with multiple possible points for action of drugs (Dickenson 2007). Different antidepressant drugs will have different mechanisms of action, not all of which are likely to be well understood, especially in terms of how a particular drug produces pain relief in any particular individual with any particular chronic pain condition (Dharmshaktu 2012; Mika 2013; Sindrup 2005). Reinforcement of the descending inhibitory pathways by increasing the amount of norepinephrine (noradrenaline) and serotonin in the synaptic cleft at both supraspinal and spinal levels is considered to be a major mechanism, as well as blockage of sodium channels. Other suggested mechanisms include postsynaptic alpha‐adrenergic, H₁‐histaminergic, and muscarinic cholinergic receptor‐blocking effects, and N‐methyl‐D‐aspartate (NMDA) antagonism (Dharmshaktu 2012).

Drugs differ in that they may have greater or lesser of each of these effects, or in some cases, the effects may be absent. This means that while antidepressant drugs may appear very similar to one another, they may have different effects on pain relief in different populations and in individuals. For example a comparison of amitriptyline with nortriptyline in one cross‐over study in PHN found that out of 31 participants five had mild or no pain with amitriptyline but moderate to severe pain with nortriptyline, while four had good pain relief with nortriptyline but none with amitriptyline (Watson 1998).

Despite the diverse and poorly understood mechanisms of action, antidepressants such as amitriptyline and duloxetine are considered to be an essential component of the therapeutic strategy for treatment of many types of neuropathic pain (Finnerup 2015; Moulin 2014; NICE 2013).

Why it is important to do this overview

There has been a large increase in the amount of information available, and substantial changes in the way we appraise studies (PaPaS 2012), which together necessitate a different approach to this topic.

Systematic reviews originally combined all antidepressant drugs at any dose in any condition, and used any definition of pain improvement as an outcome, largely because of the paucity of available data from randomised trials (McQuay 1996; Saarto 2007). A number of developments have changed this approach. First, for drugs such as duloxetine, there have been large modern studies performed to high standards, so the amount of evidence has increased (Lunn 2014; Moore 2014c). There have also been major developments in the understanding of the requirements for evidence to be trustworthy and reliable (Moore 2010a; Moore 2012b), all of which are now included in the authors' reference guide for the Pain, Palliative, and Supportive Care Review Group, to be additional requirements above those of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Neuropathic pain can be seriously disabling and is difficult to treat, but we know that effective pain relief is associated with large improvements in associated symptoms such as depression, fatigue, sleep problems, quality of life, and work (Hoffman 2010; Moore 2010b).

A number of individual reviews of antidepressant versus placebo in neuropathic pain conditions have been completed, using these new methodological criteria. An overview is required to facilitate indirect comparisons between individual drugs, providing estimates of relative efficacy that can help to inform treatment choices.

Objectives

To provide an overview of the relative analgesic efficacy of antidepressants compared with placebo or other active treatments in neuropathic pain, and to report on adverse events associated with their use.

Methods

Criteria for considering reviews for inclusion

We will include all Cochrane reviews of randomised, controlled double‐blind trials (RCTs) of antidepressant drugs for the treatment of neuropathic pain conditions.

Search methods for identification of reviews

Reviews to be included are known to the authors and published in the Cochrane Database of Systematic Reviews; there will be no additional searching for reviews. However, brief searches will be conducted to evaluate the potential evidence available for antidepressant drugs that may be used for treating neuropathic pain, but for which no Cochrane reviews had been found. This will be done to advise the potential for future Cochrane reviews.

Data collection and analysis

Two review authors will independently select reviews for inclusion, carry out assessment of methodological quality, and extract data. We will resolve any disagreements by discussion, involving a third review author if necessary.

Selection of reviews

Included reviews will assess RCTs evaluating the effects of an antidepressant drug given for relief of moderate to severe neuropathic pain, compared with placebo or a different active treatment, and will include:

1. details of inclusion and exclusion criteria;

2. details of databases searched and relevant search strategies;

3. patient‐reported pain relief; and

4. summary results for at least one desired outcome.

Data extraction and management

We will extract data from the included reviews using a standard data extraction form, using original study reports only if specific data are missing.

We will collect information on the following:

1. number of included studies and participants;

2. drug, dose, and any dose‐escalation strategy that might be relevant;

3. painful condition (eg PDN, PHN, HIV‐neuropathy).

We will extract information on risk ratio (RR) and numbers needed to treat for an additional beneficial outcome (NNT), to prevent an event (NNTp), and an additional harmful outcome (NNH) or calculate these for the following.

Primary outcomes

1. Participant reported pain intensity reduction or pain relief of 30% or greater.

2. Participant reported pain intensity reduction or pain relief of 50% or greater.

3. Patient global impression of change (PGIC) much or very much improved.

4. PGIC very much improved.

These outcomes will also be extracted when reported as moderate or substantial improvement according to the relevant Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) criteria (Dworkin 2008).

Secondary outcomes

1. Withdrawals due to adverse events.

2. Withdrawals due to lack of efficacy.

3. Participants experiencing any adverse event.

4. Participants experiencing any serious adverse event.

5. Specific adverse events, such as somnolence and dizziness, as reported.

Assessment of methodological quality of included reviews

Quality of included reviews

We will assess each included review to determine if it satisfies the criteria specified in the 'assessment of multiple systematic reviews' (AMSTAR) measurement tool for rigorous methodological quality (Shea 2007).

Each review will be required to:

1. provide an a priori design;

2. carry out duplicate study selection and data extraction;

3. carry out a comprehensive literature search;

4. include published and unpublished studies irrespective of language of publication;

5. provide a list of studies (included and excluded);

6. assess and document the scientific quality of the included studies;

7. use the scientific quality of the included studies appropriately in formulating conclusions;

8. use appropriate methods to combine the findings of studies; and

9. state conflicts of interests.

For each review, we will assess the likelihood of publication bias by calculating the number of participants in studies with zero effect (relative benefit of one) that would be needed to give an NNTB too high to be clinically relevant (Moore 2008). In this case, we will consider an NNT of 10 or above for the outcome of participant reported pain relief of 30% or greater to be the cut‐off for clinical relevance. We use this method because statistical tests for presence of publication bias have been shown to be unhelpful (Thornton 2000).

Quality of evidence in included reviews

Pre‐specified inclusion criteria state that all included reviews must use only primary studies that are both randomised and double‐blind, so minimising the risk of bias from these items. All must also include only participants with at least moderate pain intensity at baseline (visual analogue scale greater than 30/100, categorical rating scale greater than or equal to 1/3, and numerical rating scale greater than or equal to 3/10), providing a sensitive assay of analgesic efficacy.

We will analyse data for each painful condition in three tiers, according to outcome and freedom from known sources of bias.

1. 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 drop‐outs, 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 1998; Moore 2010a; Moore 2012a; Moore 2012b). We will report these first‐tier results first.

2. The second tier will use data from at least 200 participants but where one or more of the first‐tier conditions above is not met (eg reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, or lasting four to eight weeks).

3. The third tier of evidence will relate 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.

Data synthesis

We will use information on the selected efficacy outcomes to draw up comparisons of analgesic efficacy, using indirect comparison of different drugs from almost identical clinical trial conditions, with placebo as a common comparator (Glenny 2005; Song 2003). It is known that direct comparison studies are almost completely absent, and probably too small to be of value, but where they impart useful observations, that will be noted.

If the selected efficacy outcomes are not provided in an individual review, wherever possible we will calculate them from the data provided. We plan no further data synthesis.

What's new

Last assessed as up‐to‐date: 17 March 2015.

Date	Event	Description
16 January 2017	Amended	This protocol has been withdrawn. See Published notes.

Contributions of authors

SD, PW, and RAM wrote the protocol.

SD, PW, and RAM will search for and select studies for inclusion and carry out data extraction.

All review authors will be involved in the analysis and in writing the full review.

Sources of support

Internal sources

• Oxford Pain Relief Trust, UK.

  General institutional support

External sources

• The National Institute for Health Research (NIHR), UK.

  NIHR Cochrane Programme Grant: 13/89/29 ‐ Addressing the unmet need of chronic pain: providing the evidence for treatments of pain

Declarations of interest

RAM has no conflicts relating to this review or any similar product.

EK has no conflicts relating to this review or any similar product.

PW has no conflicts relating to this review or any similar product.

SD has no conflicts relating to this review or any similar product.

TRT has no conflicts relating to this review or any similar product.

NBF has no conflicts relating to this review or any similar product.

NA has no conflicts relating to this review or any similar product.

ML has no conflicts relating to this review or any similar product.

For transparency, 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.

Notes

At January 2017, this protocol has been withdrawn as it will now form part of a separate non‐Cochrane overview on drugs for neuropathic pain.

Withdrawn from publication for reasons stated in the review