GUIDELINE ON CLINICAL MEDICINAL PRODUCTS INTENDED FOR THE TREATMENT OF NEUROPATHIC PAIN 

DRAFT REVISION* AGREED BY THE EFFICACY WORKING 

PARTY 11 January 2006 

ADOPTION BY CHMP FOR RELEASE FOR CONSULTATION 26 January 2006 

END OF CONSULTATION (DEADLINE FOR COMMENTS) 31 July 2006 

AGREED BY THE EFFICACY WORKING PARTY 9 January 2007 

ADOPTION BY CHMP 24 January 2007 

DATE FOR COMING INTO EFFECT 31 July 2007 

This guideline replaces guideline: CPMP/EWP/252/03 

INTRODUCTION (BACKGROUND) 

This document intends to give guidance on the investigation of medicinal products to be used in 

central and peripheral neuropathic pain treatment. Neuropathic pain is present in a considerable 

number of patients and was referred to affect 1% of the general population by some authors. 

Neuropathic pain can be defined as pain initiated or caused by a primary lesion or dysfunction in the 

nervous system (International Association for the Study of Pain, IASP) although some experts 

(European Federation of Neurological Societies, EFNS) proposed a narrow definition excluding the 

word “dysfunction”. This definition includes pain generated at both peripheral or central nervous 

system. In contrast to the nociceptive pain these persistent pain syndromes offer no biological 

advantage (i.e., protective role). They result from the damage to the nervous system (i.e. peripheral 

nerve, the dorsal root ganglion or dorsal root, or the central nervous system) leading to peripheral or 

central neuropathic pain. Although a clear separation between central and peripheral neuropathic pain 

has been established, secondary modifications in the central nervous system were described after 

peripheral nerve damage, and these cellular alterations subsequently give rise to neuroplastic changes 

with somatosensory implications.  

In addition to the way that the patients usually describe this type of pain (sharp, shooting, electric, 

burning, stabbing) that could fluctuate, these syndromes comprise a complex combination of 

symptoms as sensory deficits, dysaesthesia, allodynia, hyperalgesia, and paraesthesia. The pain may 

be more or less persistent, fluctuating in time or even periodic which might be quite unpredictable 

(e.g. postherpetic neuralgia). Neuropathic pain within the frame work of (poly)neuropathy usually is 

accompanied by a loss of sensory/motor functions. 

Neuropathic pain may be associated with mood changes, sleep disturbance, fatigue and may have an 

impact on physical and social functioning.  

One of the most frequent classifications for neurophatic pain is based on its aetiology that can be 

metabolic, traumatic, infectious, ischaemic, hereditary, toxic, immune-mediated, idiopathic, and 

compressive. This approach of neuropathic pain has been used in most clinical trials and reports 

published to date. This taxonomy as well as others, e.g., anatomical classifications, could be criticised 

as although it can be useful for the differential diagnosis it offers no framework for clinical 

management of the pain as diverse diseases may operate through common mechanisms, no pain 

mechanism is an inevitable consequence of a particular disease process and there are no predictors to 

indicate which patient will develop neuropathic pain.  

The current knowledge about neurophatic pain suggests that the optimal treatment for this pain would 

be based on the identification of the underlying mechanism in each patient. As no specific diagnostic 

tools are available today to accomplish this goal (i.e., instruments that can disclose the different pain 

mechanisms involved in each patient), the efficacy data obtained from the clinical trials in neuropathic 

pain are based on a causal factor classification. As different disease processes could generate similar 

pain mechanisms we can expect that the efficacy data from a studied treatment can be extrapolated to 

clinical situations with different causal factors (See section 3.2). Although symptoms alone are not 

useful to define treatment strategy because they are not equivalent to mechanisms, the investigators 

are encouraged to develop innovative approaches in clinical trials (e.g. selection based on specific 

symptoms) as they could be important in the assessment of the disease progression and treatment 

outcome as well as to maximise the chance of discovering mechanism-specific treatments. New and 

innovative diagnostic tools are also encouraged in order to investigate drugs that act on in specific 

mechanisms provided that they have clinical objective application. These different approaches could 

be fruitful in order to individualise pain treatments. 

Neuropathic pain is one of the most difficult types of pain to treat. Treatment of neuropathic pain has 

been shown to be therapy resistant and if an effect is observed it is may be transient. Patients with 

neuropathic pain do not respond to non-steroidal anti-inflammatory drugs and resistance or 

insensitivity to opiates has been considered a hallmark but more recently there is controversy about the 

frequency of this characteristic. Patients have been treated with tricyclic antidepressants, serotonin and 

norepinephrine uptake inhibitors, and anticonvulsants with limited efficacy and some undesirable 

adverse-events. Other potential efficacious medicinal products with different mechanisms of action, 

some of them not completely understood, were described. Non-pharmacological treatments have been 

used with some degree of success (functional neurosurgery, dorsal column and brain stimulation, 

transcutaneous nerve stimulation, magnet therapy, psychological and occupational therapy). The local 

anaesthetic blocks have short-lived effect and long lasting blocks with phenol or cryotherapy could 

have irreversible consequences. 

1. CHARACTERISTICS OF THE DISEASE AND SELECTION OF PATIENTS 

Diagnosis 

The diagnosis should be based on clinical history and examination. The data collection should take 

into account the pain characterisation and location of the pain and also negative and positive 

phenomena (sensory findings) associated with the neuropathic pain as the diagnosis of a painful 

neuropathy rests heavily on the clinical evaluation. 

The sensory abnormalities should be evaluated with validated instruments. Standardised tests should 

be employed (e.g. von Frey filaments device or standardised thermal device). This quantitative 

sensory testing can be helpful to quantify the effects of treatments on allodynia and hyperalgesia and 

may reveal differential efficacy of treatments on different pain components. A survey of the 

distribution of pain (e.g. patient pain drawing) is encouraged as a spread of pain outside of the area of 

neurological damage could be considered a diagnostic clue of central sensitisation. 

Electrophysiological variables may be altered in medical conditions that are accompanied by 

neuropathic pain  (e.g. compressive syndromes, polyneuropathy). However, they do not correlate with 

pain progression (improvement or worsening). Accordingly, electrophysiological studies are 

considered useful tools to clarify the aetiology but they should not be used as part of the diagnostic 

process to characterise the pain itself. 

Selection of patients and inclusion criteria 

The severity is mainly evaluated by the intensity of pain that should be based on appropriate pain 

measurement scales e.g. visual analogue scale (i.e. VAS) or 11-point Likert numerical rating scale 

(NRS).  

Clinical trials should preferably include patients with moderate (i.e. VAS ≥ 40 mm or NRS ≥ 4) to 

severe pain as in a mild pain population a high response to placebo can be expected. Nevertheless, 

patients with mild pain, in addition to moderate or severe pain, are also acceptable in clinical 

confirmatory trails. 

Since neuropathic pain is usually chronic, duration of pain before enrolment is an important factor. 

Pain should be present for more than 3 months in patients that qualify for enrolment in clinical trials. 

As electrophysiological variables and sensory evaluation do not correlate with the severity of 

neuropathic pain these evaluations cannot be used as primary efficacy parameters. However, these 

variables may provide criteria for stratification. 

Co-morbidity 

Diseases with mixed pain components (e.g. cancer) should be excluded in confirmatory trials. Mood 

changes, sleep disturbance and functional capacity may change pain perception and therefore might 

affect efficacy assessment. They should therefore be assessed with appropriate and justified tools in 

order to allow an assessment of the impact of these confounders on the observed treatment effect. 

If the tested drug has antidepressant properties patients with depression should be excluded. 

Concomitant Therapy 

As in pain in general, special attention should be given to concomitant medications or 

non-pharmacological pain management techniques. Any other treatments that can modulate the 

perception of pain (i.e. physical techniques, surgery, and psychological support) should be avoided 

during the trial or remain stable during the trial if unavoidable. Appropriate washout periods of 

previous concurrent co-medication should be allowed to elapse before the study entry. A full 

assessment on homogeneity of the population between control and active groups should be based on 

provided data. 

The previous exposure and response of the trial population to analgesic agents or pharmacological 

interventions that could modulate neuropathic pain (e.g. anti-arrhythmics, anticonvulsants, 

N-methyl-D-aspartate antagonists, serotonin-norepinefrine reuptake inhibitors, clonidine, tramadol) 

should be discussed, as this information is relevant to the interpretation of results. A predefined 

subgroup analysis of previous responders/non-responders might be necessary. 

If rescue medication is allowed, the use of this medication should be documented and its impact on the 

results should be taken into account in the analysis. 

Changes in therapeutic agents that can interfere with the disease progression (e.g. antidiabetics, 

antivirals) are confounding factors and difficult to interpret. Therefore these should be kept stable for 

the duration of the trial. 

Exclusion Criteria 

Among the usual exclusion criteria in clinical trials the following ones should be considered: major 

depression; significant neurological or psychiatric disorders unrelated to neuropathic pain and that 

could interfere with pain assessment; other severe pain that might impair the assessment of 

neuropathic pain. Diseases with mixed pain components should be excluded in the confirmatory trials. 

2. METHOD TO ASSESS EFFICACY AND SENSORY VARIABLES 

Unidimensional pain scales (e.g. VAS and 11-point Likert NRS) have been extensively used and 

validated for somatic and neuropathic pain. 

Several multidimensional assessment tools may also be used for assessing the neuropathic pain as they 

evaluate different domains of neuropathic pain that are important for its characterisation and 

evaluation. Some scales were specifically developed or were used to evaluate neuropathic pain. 

Among these are the Neuropathic Pain Scale (NPS), Neuropathic Pain Symptom Inventory (NPSI), 

(SF)McGill Pain Questionnaire. However, these scales have only been partially validated because they 

are recent or not yet widely used. The assessment scale used should be validated for use in neuropathic 

pain.  

Dysaesthesia, allodynia or hyperalgesia may be assessed as supportive evidence for efficacy provided 

the assessment instruments of these conditions are valid and justified. The pain evoked by the different 

tests should be recorded separately with appropriate scales (e.g. VAS or 11-point Likert NRS). 

Efficacy Endpoints in confirmatory trials 

Primary endpoints 

Primary endpoints may include the assessment of pain intensity by simply scales as VAS or 11-point 

Likert NRS or a multidimensional assessment toll provided it is validated for neuropathic pain  

Irrespective which endpoint is chosen as primary, an observed effect on a uni-dimensional scale 

should be consistent with the observed effect on a multidimensional or visa-versa. 

It is recommended to define responders, for an assessment of proportions of patients with a clinical 

relevant reduction in pain score. Subjects with a 30% to 50% reduction in assessment scale as 

compared to baseline are considered responders. The between treatment groups comparison of 

responder rates is recommended as primary end-point of the confirmatory studies. A sensitive analysis 

is expected for different cut-off points in the responder definition. In addition other responder 

definitions, like a 2-point reduction on pain intensity as compared to baseline (0-10 scale), could be 

subject of a sensitive analysis. 

Secondary endpoints  

Secondary endpoints may include evaluation of dysaesthesia, allodynia, or hyperalgesia, changes 

stimulus evoked pain, mood, sleep, patient’s global assessment, functional and social performance 

scales and quality of life scales. The applicant should justify the choice of the most appropriate 

assessment tool to each selected endpoint. Assessment tools for secondary endpoints should be 

validated and tests for stimulus evoked pain, allodynia, or hyperalgesia should employ standardised 

quantitative sensory testing by calibrated devices. 

Simple pain scales (e.g. VAS or NRS) may be used assess ongoing, paroxysmal and evoked pain 

intensity. 

Electrophysiologic variables are not considered appropriate endpoints. 

Depending on the secondary study aims, secondary end points will need a prioritisation to account for 

multiplicity in subsequent testing. 

Timing of assessment 

The temporal aspects of the painful condition should be taken into consideration as some situations are 

intermittent/paroxysmal (ex. trigeminal neuralgia) and others are continuous and sometimes with 

superimposed paroxysmal symptoms. In addition some patients experienced mainly evoked pain. 

The use of appropriate designed diaries is acceptable. Attention should be paid to effects of recall pain 

and diary protocol adherence (e.g. timely completion of diary entries) in order to avoid bias on pain 

evaluation. Assessment of the chosen end points by mean of a diary is accepted. 

Timing of efficacy evaluation should be justified by the applicant and standardised across the 

confirmatory trials. The evaluation of efficacy in the morning and in the evening (the same day) may 

be preferable. 

3. STRATEGY AND DESIGN OF CLINICAL TRIALS 

3.1 Early Studies in Man 

Pharmacodynamics 

The CNS (Central Nervous System) effects of the product that could interfere with the reliable 

evaluation of pain (e.g. sedation, antidepressant effects) or safety should be characterised 

(i.e. identified). Effects on positive or negative phenomena (sensory findings) should also be assessed, 

e.g. in appropriate human surrogate models of neuropathic pain. 

Pharmacokinetics/Interactions/considerations in special populations (e.g. patient with renal or 

hepatic impairment) 

The pharmacokinetics of the drug should be investigated following the existing guidelines. In addition, 

appropriate studies should be conducted according to the intended indications, treatment duration, 

 administration route, delivery system and target population. The clinical confirmatory trials should be 

performed in accordance with these data. 

Interaction studies should be performed in accordance with the existing guidelines (e.g. Note for 

Guidance on the investigation of drug interactions). 

Dose-Response Studies 

Although many of the medicinal products that could be useful in the treatment of neuropathic pain 

come from other therapeutic fields with appropriate dose-finding and clinical trials for other 

indications, this does not preclude the need for appropriate dose finding studies in neuropathic pain 

unless appropriate justification is given considering both efficacy and safety reasons. 

Well-planned dose response studies should be carried out. A dose-response curve analysis, taking into 

consideration the adverse reactions, is helpful in these studies. Appropriate doses should be used in 

clinical trials to minimise the adverse events, whilst producing a useful level of pain relief. A placebo 

arm is needed. 

These studies, whenever this is the case, should provide appropriate information about the dose 

titration schedule to reach the stable therapeutic dose with minimum side effects. The need of a 

titration period will increase the study duration (see below). 

The Note for Guidance on Fixed Combination Product should be followed if fixed combinations are 

tested. 

3.2 Therapeutic Confirmatory Studies 

Study design 

Randomised, double blind, placebo controlled studies are required to establish efficacy in neuropathic 

pain. 

Neuropathic pain is usually present as a chronic situation and the study duration should take this in 

consideration. 

As there is an increasing number of drugs approved for neuropathic pain, in those clinical conditions 

for which there is an established treatment option a three-arm study (study drug – comparator - 

placebo) should be provided in order to allow the assessment of comparative efficacy and safety of a 

new product. 

The use of more than one type of rescue medication is discouraged. Appropriate conditions for use of 

rescue medication should be defined in the protocol. The protocol should also define how the impact 

of rescue medication on observed treatment differences is analysed. 

Add-on studies, on a stable but insufficient background therapy, are allowed (refer to section I) but the 

indications supported by these studies may well be limited to the tested add-on regimen. The supposed 

mechanism of action of the tested drug should differ from the agent were it is added to. 

The clinical pivotal trials might incorporate more than one fixed dosage arm. The arm that supports 

the proposed treatment regimen should have an acceptable number of patients. 

Target population 

The population enrolled in the clinical studies should be in accordance with the claimed indication. 

The currently most well established neuropathic pain clinical situations are post-herpetic neuralgia, 

painful diabetic neuropathy, trigeminal neuralgia and post-stroke pain. Other types of peripheral and 

central neuropathic pain situations are also acceptable if adequately characterised in study protocol 

and justified. Clinical situations with mixed pain origins (e.g. somatic and neuropathic) could be 

considered in non-pivotal supportive studies. 

Studies conducted in only one pain clinical situation can only support an indication restricted to the 

specific condition (e.g. post-herpetic neuralgia, post-stroke pain syndrome). For the claim “peripheral 

neuropathic pain”, the efficacy of the tested drug should be shown in more than one clinical situation 

of peripheral neuropathic pain (e.g. post-herpetic neuralgia, painful diabetic neuropathy), for the claim 

“general neuropathic pain”, the efficacy of the tested agent should be shown in a central pain model 

(e.g. post-stroke pain) in addition because although central mechanisms could be involved in 

peripheral naturopathic pain, peripheral mechanisms are not involved in central neuropathic pain. 

The applicant should justify the route of administration taking into consideration the target population. 

As a rule the simplest route of administration for the intended objective is to be used. 

Choice of control 

Randomised controlled studies against placebo are required. In cases that there exists a established 

treatment option a third arm with the active comparator is required (please refer to sub-heading study 

design). Strategies to reduce the number of patients enrolled in placebo arm could be allowed provided 

that study still rests adequately powered. 

Study duration 

The study duration should be at least 12 weeks after a stable dose is achieved in order to exclude a 

transient effect. 

Maintenance and/or development of tolerance should be tested, for instance in an open label extension 

phase during 6 to 12 months without placebo. The quality of the assessment and monitoring should be 

similar to that the double blind phase. Alternatives study designs are acceptable. 

Methodological considerations before initiation of the study (e.g. sample size, stratification) 

Efficacy should be studied in a homogenous population that is homogenous with respect to either 

diagnosis or symptom configuration (see 3.2 Therapeutic Confirmatory Studies under Target 

population). 

Stratification according baseline disease patient characteristics is to be considered whenever 

necessary. Patients submitted to other neuropathic pain treatments during the trial, i.e. introducing new 

treatments or modifications of otherwise stable treatments should be assessed as non-responders. 

Although mood and physical and social functioning, are important variables in neuropathic pain, if the 

aim of the study is to demonstrate improvement in other areas other than pain intensity itself, 

e.g. sleep and function, the study should be planned according to these objectives. These studies could 

be seen as supportive studies rather than pivotal studies.  

Statistical analysis and reporting of the results, with consideration on the expected clinical 

benefit if relevant 

The existing guidance (e.g. E9: Statistical Principles for Clinical Trials) should be followed. 

Concomitant pain treatments and factors that can modify pain are to be considered in the efficacy 

analysis. For instance mood change, sleep disturbance and fatigue may change pain perception and 

therefore might affect efficacy assessments. The impact of concomitant rescue medication on the 

observed magnitude of the effect should also be taken into account in the efficacy analysis. 

Some adverse events associated with specific drugs (e.g., dizziness and somnolence) could modify 

pain perception. The impact of these adverse events on the observed magnitude of the effect should be 

evaluated. In addition, it may unblind patients or physicians to treatment assignment. This should be 

evaluated as well. 

The impact of concomitant rescue medication on the observed magnitude of the effect should be taken 

into account in the efficacy analysis. 

3.3 Studies in special populations 

Children 

There is very little information with regard to children and neuropathic pain. 

The more frequent neuropathic pain models in adult studies, i.e. post-herpetic, diabetic 

polyneuropathy and post-stroke pains are very rare in children. Neuropathic pain in children and 

adolescent represents a heterogeneous group of pain with various aetiologies. The more frequent are 

traumatic neuropathic pain, phantom pain, obstetrical brachio-plexus lesion and post anti-neoplastic 

treatment pain (e.g. vincristine). There is a lack of epidemiological data to estimate the prevalence of 

 those pains in children, even if overall they are not very rare. Even without a full knowledge of 

maturation of the CNS, it is not expected that there is a difference in mechanism of neuropathic pain 

between adults and adolescents. 

In view of the heterogeneicity of neuropathic pain in children and adolescent, it is recognised that 

clinical development might be difficult. When sufficient information to demonstrate efficacy and 

safety in paediatric patients cannot be obtained, pharmacokinetic data may form the bases of the dose 

recommendations in children, if proper justified. 

Furthermore, investigation of efficacy of a product in models common to both adults and children 

(e.g. phantom pain) is encouraged where possible in order to better know how efficacy data can be 

extrapolated from adults to children or from one model to another. 

Long-term safety data are required when chronic use is foreseen. The impact of treatment on growth 

and endocrine development, need to be evaluated. In addition if the safety profile indicate an effect 

cognitive function (e.g. sedation, concentration disturbances), long-term safety data on cognitive 

function may be required. 

Elderly 

Most studies will be performed in patients with a relatively high age. Pharmacokinetic data and a 

separate analysis of the elderly in the database may be sufficient (see ICH E7). 

Careful attention should be paid to adverse events associated with some drug classes that have been 

used to treat neuropathic pain and that could be more frequent and intense in the elderly (e.g. opioids, 

tricyclic antidepressants). 

4. CLINICAL SAFETY EVALUATION 

4.1 Specific adverse events to be monitored 

Assessment of the potential adverse events (AE) according to the mechanism of action should be 

performed using a systematic and planned methodology. 

Specific problems associated to some class of drugs that have been used in neuropathic pain 

management should be systematically evaluated: opioids, e.g. tramadol (nausea, constipation, 

somnolence, dizziness); tricyclic antidepressants (myocardial infarction, overall mortality, adverse 

events increase with concomitant use of cardiac medications, sedation, anticholinergic effects); 

antiepileptic drugs (rash, sedation, dizziness, nausea). 

Any other AE predicted by the pharmacodynamic properties of new investigational products should be 

evaluated and analysed according a pre-planned methodology. 

Bias introduced by concomitant medication should be recognised and controlled as far as possible in 

control and active groups. 

Potential detrimental effects of the drug under study in the specific disease associated with 

neuropathic pain (e.g., diabetes and glycemic control) should be actively investigated. 

The monitoring of adverse events related to the pharmacodynamics of the studied drug should be 

conducted according to the existing ICH guidelines. 

The investigation of tolerance is of outstanding importance on the treatment of chronic neuropathic 

pain. Withdrawal and rebound effects after drug discontinuation should also be evaluated during a pre- 

determined period monitoring the pain intensity and adverse events. 

As for other medicinal products the AE need to be fully documented by body system. Any groups at 

increased risk of AE for should be identified. 

The ICH/EU E1A guideline  (Extent of Exposure to Access Clinical Safety for Drugs Intended for 

Long-Term Treatment of Non-Life-Threatening Conditions) should be followed in addition to other 

relevant guidance. 

4.2 Extent of population exposure to assess clinical safety 

The ICH/EU E1A guideline  (Note of Guidance on Population Exposure: the Extent of Population 

Exposure to Assess Clinical Safety) should be followed in addition to other relevant guidance. 

4.3 Long-term safety 

Safety data from 12 months clinical studies should be available in the population aimed by the claimed 

indication. 

5. OTHER INFORMATION 

In order to harmonise the technical language in the clinical trials the CHMP encourages the use of the 

definitions proposed by the International Association for the Study of Pain.