Nerve growth factor for neuropathic pain

Abstract

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

To assess the analgesic efficacy and adverse effects of nerve growth factor for chronic neuropathic pain.

Background

Neuropathic pain can be a consequence of damage to or dysfunction of the nervous system and be either spontaneous or evoked by a stimulus. Neuropathic pain is a very common symptom in clinical practice that is difficult to treat and affects millions of people all over the world. In spite of the increase in clinical trials of treatments for neuropathic pain in recent years, pain relief is not always satisfactory and pharmacological treatment is often ineffective.

Description of the condition

According to the 2011 International Association of the Study of Pain, the definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011; Treede 2008). Nerve damage may cause neuropathic pain, but changes in the central nervous system (CNS) often follow (Moisset 2007). About two million people in the USA are estimated to suffer from neuropathic pain (Foley 2003). In Europe, neuropathic pain is reported to affect as many as seven to eight per cent of the general population (Bouhassira 2008; Torrance 2006), and about seven per cent according to a systematic review of studies published since 2000 (Moore 2013a). Neuropathic pain often causes depression, insomnia, fatigue, and decreased socialisation; it has a significant negative impact on quality of life (Jensen 2007).

Neuropathic pain may be spontaneous (stimulus‐independent) or evoked (stimulus‐dependent). Spontaneous pain can be experienced as aching, burning, shooting, lancinating, prickling, or electrical. Evoked or stimulus‐dependent neuropathic pain can be characterised by allodynia and hyperalgesia (Sah 2003). Allodynia is pain elicited by a non‐noxious stimulus, and hyperalgesia is characterised as an increased pain response to a noxious stimulus (Woolf 1999).

Mechanisms of neuropathic pain are complex and commonly involve the following.

1. Aberrant sprouting of Aβ fibres into the pain layers (laminae I and II) of the dorsal horn in the spinal cord, resulting in pain from non‐noxious stimuli (Woolf 1999).

2. Ectopic discharges from injured C‐fibres (Wu 2002).

3. Increased release by injured sensory neurons of excitatory amino acids, which enhance spinal responses to nociceptive stimulation (Sah 2003).

4. Activation of central pathways such as the rostral ventromedial medulla, a region crucial to the modulation of nociception (Sah 2003).

Neuropathic pain is 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, combining pharmacological interventions with physical or cognitive interventions, or both. Although conventional analgesics are usually held not to be effective, there is no evidence to support or refute that view. Some people may derive benefit from a topical lidocaine patch, though the quality of evidence is very low (Derry 2014). So‐called unconventional analgesics, such as antidepressants like duloxetine and amitriptyline (Lunn 2014; Moore 2012a; Sultan 2008), or antiepileptics, such as gabapentin or pregabalin (Moore 2009; Moore 2011; Wiffen 2013), are often used in treatment. Recent guidelines tend to be generally in agreement about treatment options (Finnerup 2015; NICE 2013). Opioid analgesics and tramadol are usually second‐line choices, although in some circumstances they can be considered for first‐line use (Dworkin 2007). Fewer than half of people with neuropathic pain achieve effective analgesia (Beal 2012). Unfortunately, adverse events and the risk of drug‐drug interactions limit the use of some of these agents (Sindrup 1999).

Description of the intervention

Nerve growth factor (NGF) is a neurotrophic factor, which belongs to a group of secreted proteins that can "support neuronal survival and growth during development of the nervous system, maintain the structural and functional integrity of the adult nervous system, and regulate plasticity of the injured or diseased adult nervous system" (Sah 2003). The same subset of neurotrophic factors also includes brain‐derived neurotrophic factor, neurotrophin‐3, and neurotrophin‐4/5 (Sah 2003). NGF binds to specific cell surface receptors to mediate neuron function. NGF promotes the survival of small fibre sensory and sympathetic neurons (Levi‐Montalcini 1987). In the last decade, there has been a growing interest in studies that demonstrate the great applied potential of NGF in neuropathic pain conditions.

How the intervention might work

NGF is an important regulator of neuronal function, differentiation, growth, survival, and death, and acts via many intracellular signalling pathways. NGF mediates neuropathic pain via two major receptor types: neurotrophic tyrosine kinase (Trk) receptors and the pan neurotrophin receptor at 75 kDa (p75NTR). Following Trk receptor and p75NTR activation, several downstream signalling mechanisms are associated with neuropathic pain (Khan 2015). NGF can directly upregulate substance P content of adult sensory neurons and modulate synaptic strength. It represents a key humoral link between inflammation and the nociceptive sensory neurons that initiate and sustain heat and mechanical hyperalgesia (Lewin 2014).

Although NGF can induce mechanical allodynia and thermal hyperalgesia in animals (Khan 2015), anti‐NGF administration has also produced significant analgesic effects in several animal pain models (Chang 2016). There is also some evidence that NGF is able to restore the spinal cord homeostatic equilibrium and maintain analgesia in neuropathic pain in animals. Intrathecal NGF can reduce allodynia and thermal hyperalgesia in neuropathic animals (Cirillo 2010; Siniscalco 2011). Investigators have reported positive effects for NGF in human clinical trials of peripheral neuropathic pain (McArthur 2000).

In all clinical trials, NGF was given by subcutaneous injection two or three times per week at the minimum dose of 0.1 μg/kg. NGF was best‐tolerated at doses less than 1 μg/kg (Apfel 1999). Some clinical trials indicated that NGF was safe and effective as a treatment for preventing progression of diabetic or human immunodeficiency virus (HIV)‐associated peripheral neuropathies at the largest dose of 0.3 μg/kg two or three times per week (Apfel 1998; Schifitto 2001); however, another trial found no significant benefit from NGF in diabetic peripheral neuropathy at the dose of 0.1 μg/kg three times per week (Apfel 2000). One of these studies showed large improvements in pain intensity following high‐dose NGF, and the effect may be dose‐dependent (Schifitto 2001).

Why it is important to do this review

Neuropathic pain tends to be chronic and may be present for months or years. Some neuropathic pain conditions, such as painful diabetic neuropathy, are common, with prevalence rates up to 400 per 100,000 person years (McQuay 2007). The prevalence of neuropathic pain in diabetes mellitus and postsurgical 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. 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 (NNTB) 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 2014).

NGF can theoretically promote or reduce neuropathic pain through its putative mechanisms and has shown mixed results in animal experiments. NGF has also produced mixed results in clinical trials conducted to investigate its efficacy and safety in people with neuropathic pain. No systematic review has been performed to clarify the conflicting areas of evidence and assess the overall potential clinical utility of NGF in this condition.

Objectives

To assess the analgesic efficacy and adverse effects of nerve growth factor for chronic neuropathic pain.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) and quasi‐RCTs with double‐blind assessment of participant outcomes on the therapeutic efficacy and safety of nerve growth factor (NGF) for neuropathic pain. Quasi‐RCTs are trials in which participants are assigned to treatment groups using methods that are partly systematic, such as by alternation, hospital record number, or date of birth. Abstracts and published or unpublished trials with sufficient data in any language will be eligible for inclusion in this Cochrane Review. We will exclude short abstracts (usually meeting abstracts).

Types of participants

We will include participants of all ages and both sexes with a diagnosis of neuropathic pain according to the definition of the International Association for the Study of Pain (IASP): "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011), regardless of cause. We will include participants with any documented pain level at the beginning of the trial.

Participants will have a diagnosis of one or more chronic neuropathic pain condition including (but not limited to):

1. cancer‐related neuropathy;

2. central neuropathic pain;

3. complex regional pain syndrome (CRPS) Type II;

4. human immunodeficiency virus neuropathy;

5. painful diabetic neuropathy;

6. phantom limb pain;

7. postherpetic neuralgia;

8. postoperative or traumatic neuropathic pain;

9. spinal cord injury;

10. trigeminal neuralgia.

Where we include studies of participants with more than one type of neuropathic pain, we will analyse results according to the primary condition.

Types of interventions

NGF given in any dose and by any route for at least eight weeks, compared with placebo, no treatment, or other treatments. We will report comparisons with placebo and with other routine treatment separately. We will allow co‐interventions provided that they are provided to each group equally.

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 the 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 (Khaliq 2007), 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).

Primary outcomes

1. Participant‐reported pain relief of 30% or greater.

2. Participant‐reported pain relief of 50% or greater.

3. PGIC much or very much improved.

4. PGIC very much improved.

Secondary outcomes

1. Any pain‐related outcome measuring improvement.

2. Withdrawals due to lack of efficacy.

3. Participants experiencing any adverse event.

4. 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 prolongs 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.

5. Withdrawals due to adverse events.

6. Specific adverse events, particularly:

   1. injection site pain;

   2. hyperalgesia.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library current issue), MEDLINE (1966 to present), and Embase.

The draft MEDLINE strategy is in Appendix 1. We will adapt the search strategy for the Cochrane Neuromuscular Specialised Register, CENTRAL, and Embase.

Searching other resources

We will search the following ongoing trials and research registers for ongoing trials and for additional reports of published trials.

1. ClinicalTrials.gov (http://clinicaltrials.gov/).

2. World Health Organization Clinical Trials Registry Platform (http://apps.who.int/trialsearch/).

3. Current Controlled Trials Register (http://www.controlled‐trials.com/).

We will check all references in any identified trials and review articles to identify additional published or unpublished data. We will search NHSEED for any economic information and DARE for any information relevant to the 'Discussion' section of the review.

Data collection and analysis

We will perform separate analyses according to particular neuropathic pain conditions.

Selection of studies

Two review authors (MZ and JG) will independently screen the titles, abstracts, and keywords of every record retrieved to identify potentially relevant trials for full review. We will obtain full‐text papers of potentially eligible studies and from them select trials for inclusion. We will document the study selection process in sufficient detail to complete a PRISMA flow chart and a 'Characteristics of excluded studies' table (Higgins 2011). We will resolve disagreement by discussion and, if necessary, we will consult a third review author (SG). There will be no limitations as to language.

Data extraction and management

Two review authors (MZ and JG) will independently extract the data from studies that meets the inclusion criteria using a specially designed data collection form and check for agreement. A third review author (SG) will resolve discrepancies.The extracted data form will include information about the pain condition and number of participants treated, drug and dosing regimen, study design (placebo or active control), study duration, follow‐up, outcome measures, results, withdrawals, and adverse events.

We will obtain missing data from the primary study investigators. If there are queries and questions regarding study data, we will contact the study author(s) to obtain more information. If an included study has more than two intervention arms, we will include only intervention and control groups that meet the eligibility criteria of the review. One review author will enter data into the Cochrane statistical software Review Manager 5 (RevMan 5) (RevMan 2014), and another review author will check the accuracy of the data entry.

We will obtain translations of papers if necessary; translators will either extract data directly into a data extraction form or provide a verbatim translation. We will crosscheck the accuracy of numerical data if possible.

Assessment of risk of bias in included studies

Two review authors (MZ and JG) will independently assess the risk of bias in each included study and complete the 'Risk of bias' table according to the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion and will consult a third review author (SG) if necessary. We will assess the following aspects.

1. Random sequence generation (selection bias)

2. Allocation concealment (selection bias)

3. Blinding of participants and personnel (performance bias)

4. Blinding of outcome assessors (detection bias)

5. Incomplete outcome data (attrition bias)

6. Selective reporting (reporting bias)

7. Other bias

We will judge the risk of bias as 'low', 'high' or 'unclear' where unclear indicates an unclear or unknown risk of bias (Higgins 2011).

We will consider blinding separately for different key outcomes where necessary (for example, for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). If there is unclear information, we will contact the study author(s) to obtain more data. Where information on risk of bias relates to unpublished data or correspondence with a trial author, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will use RevMan 5 to perform analyses (RevMan 2014). We will calculate the number needed to treat for an additional beneficial outcome (NNTB) as the reciprocal of the absolute risk reduction (ARR; McQuay 1998). For unwanted effects, the NNTB becomes the number needed to treat for an additional harmful outcome (NNTH) and is calculated in the same way. For dichotomous data, we will use risk ratios or risk differences with a 95% confidence interval. We will not use continuous data in analyses.

Unit of analysis issues

For every study identified, we will assess the risk of bias and take it into consideration in the analysis. If the data are from a non‐standard design study, we will manage the data according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will split the control treatment arm between active arms in a single study if the active treatment arms are not combined for analysis.

Dealing with missing data

We will undertake an intention‐to‐treat (ITT) analysis where the ITT population consists of participants who were randomised, took at least one dose of assigned study medication, and provided at least one post‐baseline assessment. We will assign missing participants zero improvement wherever possible.

Assessment of heterogeneity

We will deal with heterogeneity by combining studies that examine similar conditions. We will assess heterogeneity among trials by using the Chi² test with a 10% level of statistical significance (P value < 0.1) and I² statistic > 50% (Higgins 2002; Higgins 2003). When the I² statistic value is greater than 50%, we will consider possible reasons for this. For trials that are clinically heterogeneous or present insufficient information for pooling, we will perform a descriptive analysis (Higgins 2011).

Assessment of reporting biases

We will use a funnel plot to test small study effects if there are at least 10 included studies. If there are insufficient studies, we will use a descriptive analysis to evaluate potential reporting biases. Although funnel plot asymmetry has been equated with publication bias, there are other causes, such as differences in methodological quality and true heterogeneity in intervention effects.

Data synthesis

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 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 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 2010; Moore 2012a; Moore 2012b). We will report these top‐tier results first.

2. 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).

3. 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.

'Summary of findings' tables

We will construct a 'Summary of findings' table using GRADEpro Guideline Development Tool (GDT) software (GRADEproGDT 2014). We will assess the quality of the evidence (high, moderate, low, or very low) for specified outcomes. We will downgrade the quality of RCT evidence depending on five factors (study design, imprecision, publication bias, heterogeneity, and inconsistency of effect), and will provide explanations for our decisions in footnotes. The included outcome measures will be the following.

1. Participant‐reported pain relief of 30% or greater.

2. Participant‐reported pain relief of 50% or greater.

3. PGIC much or very much improved.

4. PGIC very much improved.

5. Withdrawals due to adverse events.

6. Participants experiencing any serious adverse event.

We will present the comparison with placebo as the primary 'Summary of findings' table and include others as additional tables.

Subgroup analysis and investigation of heterogeneity

We will report results for different types of neuropathic pain separately. If there are sufficient data on different NGF doses, we will perform subgroup analyses for our primary outcome.

Sensitivity analysis

We will perform the following sensitivity analyses.

1. repeat the analysis after omitting studies at high risk of bias in specific domains, for example studies that lack allocation concealment or blinding.

2. if there are very large studies, repeat the analysis excluding them to look at how much they dominate the results.

Reaching conclusions

We will base our conclusions only on findings from the synthesis of included studies for this Cochrane Review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline the remaining uncertainties are in the area.

Appendices

Appendix 1. MEDLINE (OvidSP) draft search strategy

Database: Ovid MEDLINE(R) <1946 to May Week 5 2015> Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 randomized controlled trial.pt. (396566) 2 controlled clinical trial.pt. (89628) 3 randomized.ab. (293430) 4 placebo.ab. (152783) 5 drug therapy.fs. (1780700) 6 randomly.ab. (206823) 7 trial.ab. (302884) 8 groups.ab. (1317074) 9 or/1‐8 (3360490) 10 exp animals/ not humans.sh. (4056152) 11 9 not 10 (2860827) 12 exp pain/ or (pain or painful).mp. (563735) 13 (nerve$ or neuropath$).mp. (603745) 14 12 and 13 (54838) 15 (neuralgi$ or hyperalgesia or allodynia or sciatica).mp. (35881) 16 14 or 15 (76268) 17 exp Nerve Growth Factors/ (39995) 18 Leukemia Inhibitory Factor/ (2633) 19 Epidermal Growth Factor/ (21642) 20 exp Somatomedins/ (36815) 21 Platelet‐Derived Growth Factor/ (11209) 22 exp Transforming Growth Factors/ (53211) 23 exp Fibroblast Growth Factors/ (25742) 24 (neurotrophic factor$ or neurotrophin$ or nerve growth factor$ or BDNF or GDNF or CNTF or leuk?emia inhibitory factor or epidermal growth factor insulin like growth factor or platelet derived growth factor or transforming growth factor or fibroblast growth factor or artemin or neurturin or persephin).mp. (161578) 25 or/17‐24 (216733) 26 11 and 16 and 25 (274) 27 remove duplicates from 26 (268)

Contributions of authors

YZ and SG completed the draft protocol and modified the protocol according to the feedback. LH, the corresponding author, developed the proposal, offered expert advice, reviewed the protocol, and is responsible for developing the review. MZ, JG and CZ helped to produce the draft of the methods section. AH corrected the English and provided professional guidance.

Sources of support

Internal sources

• West China Hospital of Sichuan University, China, Other.

External sources

• None, Other.

Declarations of interest

YZ: none known.

SG: none known.

LH: none known.

MZ: none known.

JG: none known.

AH: received compensation for serving as Editor‐in‐Chief of Experimental Neurology and Associate Editor for Annals of Clinical and Translational Neurology. He received grants from the National Institutes of Health (NIH), DOD, Maryland TEDCO, the Adelson Foundation for Medical Research, and the Foundation for Peripheral Neuropathy. He also served as an expert witness on a legal case and consulted with Neurocrine to review preclinical animal toxicology data.

CZ: none known.

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