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## Complete Summary

#### GUIDELINE TITLE

EFNS guidelines on pharmacological treatment of neuropathic pain.

#### BIBLIOGRAPHIC SOURCE(S)

Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio
C, Sindrup S, Wiffen P, EFNS Task Force. EFNS guidelines on
pharmacological treatment of neuropathic pain. Eur J Neurol 2006
Nov;13(11):1153-69. \[147 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17038030)

#### GUIDELINE STATUS

This is the current release of the guideline.

The European Federation of Neurological Societies (EFNS) Task Force
plans to update these guidelines in 2 years.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [December 12, 2007,
    Carbamazepine](http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine):
    The U.S. Food and Drug Administration (FDA) has provided
    recommendations for screening that should be performed on specific
    patient populations before starting treatment with carbamazepine.

-   [May 2, 2007, Antidepressant
    drugs](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Antidepressant):
    Update to the existing black box warning on the prescribing
    information on all antidepressant medications to include warnings
    about the increased risks of suicidal thinking and behavior in young
    adults ages 18 to 24 years old during the first one to two months of
    treatment.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Neuropathic pain, including:

-   Painful polyneuropathy (PPN)

-   Postherpetic neuralgia (PHN)

-   Trigeminal neuralgia (TN)

-   Central pain (CP)

-   Other neuropathic pain conditions

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Internal Medicine\
Neurology\
Pharmacology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

-   To examine all the randomised controlled trials (RCTs) performed in
    the various neuropathic pain conditions

-   To evaluate the drug effects on pain symptoms, quality of life, and
    sleep, and the adverse events

-   To propose recommendations based on the results of these trials
    aiming at helping clinicians in their treatment choice for most
    neuropathic pain conditions

-   To propose new studies that may help clarify unsolved issues

#### TARGET POPULATION

Patients with neuropathic pain

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Painful Polyneuropathy**

1.  First line treatment: gabapentin, pregabalin, tricyclic
    antidepressants (TCA)

2.  Second/third line treatment: lamotrigine, opioids,
    serotonin-noradrenalin reuptake inhibitors (SNRIs), tramadol

**Postherpetic Neuralgia**

1.  First line: gabapentin, pregabalin, topical lidocaine, TCA

2.  Second/third line: capsaicin, opioids, tramadol, valproate

**Trigeminal Neuralgia**

1.  First line: oxcarbazepine, carbamazepine

2.  Second/third line: surgery

**Central Pain**

1.  First line: amitriptyline, gabapentin, pregabalin

2.  Second/third line: cannabinoids, lamotrigine, opioids

**Note**: Refer to the \"Major Recommendations\" field for information
on other medications with level C rating and weak/discrepant results
with level A/B evidence.

#### MAJOR OUTCOMES CONSIDERED

-   Effectiveness of treatment in pain relieving and improving quality
    of life, sleep, and comorbidities

-   Side effects of medications

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases\
Searches of Unpublished Data

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

The Task Force conducted an initial search through the central database
in the Cochrane Library. Whenever the Cochrane search failed to find top
level studies for a given neuropathic pain condition or a drug which was
supposedly active on neuropathic pain, the Task Force expanded the
search using Medline and other electronic databases (1966--to date), and
checking reference lists published in meta-analyses, review articles,
and other clinical reports. Furthermore, to get the most updated
information, the task Force also asked all the pharmaceutical companies
producing drugs in this field to provide them with studies not yet
published (refer to Appendix A in the original guideline document). Any
reports retrieved from these contacts were pooled with the others for
selection.

**Inclusion and Exclusion Criteria**

Included studies complied with the following criteria: (1) randomized or
non-randomized but controlled class I or II trials (lower-class studies
were evaluated in conditions in which no higher-level studies were
available); (2) pain relief considered as a primary outcome and measured
with validated scales; (3) minimum sample of 10 patients; (4) treatment
duration and follow up clearly specified; (5) treatment assessed in
repeated dose settings for at least 1 week; (6) treatment feasible in an
outpatient setting (intravenous \[i.v.\], subcutaneous, or intrathecal
therapy or nerve blocks were not considered); (7) evaluating currently
used drugs or drugs under clinical phase-III development: (8) including
patients with pain secondary to a definite nervous system lesion/disease
or idiopathic trigeminal neuralgia \[TN\]; (9) full paper citations in
English, Danish, French, Finnish, German, Italian, Portuguese or
Spanish.

Exclusion criteria were duplicated patient series, uncontrolled studies,
pain without evidence of a nerve lesion, such as atypical facial pain,
Complex Regional Pain Syndrome (CRPS) type I or low back pain,
non-validated or unconventional outcome measures, non-pharmacological
intervention, treatments acting directly on the disease or pre-emptive
treatments.

**Information Selected from the Trials**

From articles meeting the search criteria, information regarding the
efficacy not only on overall pain and main side-effects was extracted,
but also effects on pain symptoms or signs, quality of life and mood,
whenever available. The Task Force also referred to recent
well-conducted meta-analyses when analysis of these studies did not
provide with additional information regarding these end-points. The NNT
(the number of patients needed to treat to obtain one responder to the
active drug) with 95% confidence intervals (CI) for class I/II studies
was used in order to gain information regarding the overall efficacy of
a drug. Unless otherwise specified, the NNT for 50% pain relief was
used. These values were calculated for newer trials or extracted from
recent meta-analyses performed by members of this Task Force or the
Cochrane database. The Number Needed to Harm was not used because of
lack of uniform criteria for assessing harmful events.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Evidence Classification Scheme for a Therapeutic Intervention**

**Class I**: An adequately powered prospective, randomized, controlled
clinical trial with masked outcome assessment in a representative
population or an adequately powered systematic review of prospective
randomized controlled clinical trials with masked outcome assessment in
representative populations. The following are required:

a.  Randomization concealment

b.  Primary outcome(s) is/are clearly defined

c.  Exclusion/inclusion criteria are clearly defined

d.  Adequate accounting for dropouts and crossovers with numbers
    sufficiently low to have minimal potential for bias

e.  Relevant baseline characteristics are presented and substantially
    equivalent among treatment groups or there is appropriate
    statistical adjustment for differences

**Class II**: Prospective matched-group cohort study in a representative
population with masked outcome assessment that meets a--e above or a
randomized, controlled trial in a representative population that lacks
one criteria a--e

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome assessment is independent of
patient treatment

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Classification of evidence and recommendation grading adhered to the
European Federation of Neurological Societies (EFNS) standards. In
particular, class I refers not only to adequate prospective randomized
controlled trials (RCTs), but also to adequately powered systematic
reviews (SRs) (see the \"Availability of Companion Documents\" field and
\"Rating Scheme for the Strength of the Evidence\" field).

The NNT (the number of patients needed to treat to obtain one responder
to the active drug) with 95% confidence intervals (CI) for class I/II
studies was used in order to gain information regarding the overall
efficacy of a drug.

Unless otherwise specified, the NNT for 50% pain relief was used. These
values were calculated for newer trials or extracted from recent
meta-analyses performed by members of this Task Force or the Cochrane
database. The Number Needed to Harm was not used because of lack of
uniform criteria for assessing harmful events.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

In order to provide the neurologist with clear indications regarding
drug treatment for the most studied neuropathic pains, the Task Force
decided to produce individual chapters for painful polyneuropathies,
postherpetic neuralgia, trigeminal neuralgia, and central pain (spinal
cord injury, post-stroke pain, and multiple sclerosis), but to search
and report also for the other less studied neuropathic conditions
(post-traumatic/post-surgical nerve lesions, phantom limb pain,
Guillain--Barre´ syndrome) and for neuropathic pains with multiple
aetiology. Each chapter was assigned to two Task Force participants.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Rating of Recommendations**

**Level A rating** (established as effective, ineffective, or harmful)
requires at least one convincing class I study or at least two
consistent, convincing class II studies.

**Level B rating** (probably effective, ineffective, or harmful)
requires at least one convincing class II study or overwhelming class
III evidence.

**Level C rating** (possibly effective, ineffective, or harmful)
requires at least two convincing class III studies.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guidelines were validated according to the European Federation of
Neurological Societies (EFNS) criteria (see \"Availability of Companion
Documents\" field in this summary).

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The levels of evidence (class I-IV) supporting the recommendations and
ratings of recommendations (A-C) are defined at the end of the \"Major
Recommendations\" field.

**Painful Polyneuropathy**

Treatments with established efficacy on the basis of class I trials in
painful polyneuropathy (PPN) (with the exception of human
immunodeficiency virus (HIV)-associated polyneuropathy) are tricyclic
antidepressants (TCAs), duloxetine, venlafaxine, gabapentin (GBP),
pregabalin, opioids and tramadol (**level A**). The balanced TCA
(amitriptyline and imipramine) at adequate dosages seem to have the
highest efficacy on the basis of NNT (the number of patients needed to
treat to obtain one responder), but most data stem from small trials
which may overestimate efficacy. The Task Force recommends TCA or
GBP/pregabalin as first choice. The serotonin-noradrenaline reuptake
inhibitors (SNRI) duloxetine and venlafaxine are considered second
choice because of moderate efficacy, but are safer and have less
contraindications than TCAs and should be preferred to TCA particularly
in patients with cardiovascular risk factors (see the \"Potential
Harms\" field). Second/third-line therapy includes opioids (potential
safety concerns in noncancer pain; see the \"Potential Harms\" field)
and lamotrigine (LTG) (**level B**). Treatments with weaker/lack of
efficacy include capsaicin, mexiletine, oxcarbazepine (OXC), selective
serotonin reuptake inhibitors (SSRIs), topiramate (**level A**),
memantine, mianserin and topical clonidine (**level B**). There is low
strength of evidence and safety concerns for carbamazepine (CBZ) (see
the \"Potential Harms\" field) (**level C**) and limited support for the
use of dextromethorphan and levodopa. Discrepant results have so far
been obtained with valproate.

*HIV-Associated Neuropathy and Chemotherapy-Induced Neuropathy*

HIV-associated polyneuropathy has been found refractory to most
currently assessed drugs. This may be due to particular mechanisms of
pain in this often progressive condition and/or to a high placebo
response, observed in many trials. Only LTG has been reported
efficacious in a subgroup of patients receiving antiretroviral therapy
(ART) in one class I trial, but a smaller class II trial reported
totally opposite results (**level B**).

**Postherpetic Neuralgia**

In postherpetic neuralgia (PHN), drugs with established efficacy include
TCAs, GBP, pregabalin and opioids (**level A, class I trials**). Drugs
with lower efficacy or limited strength of evidence include capsaicin,
tramadol, topical lidocaine, and valproate (**level B**). The Task Force
recommends TCAs or GBP/pregabalin as first line. Topical lidocaine has
been evaluated only in patients with allodynia in short-term studies
which used an enrichment phase or were post-hoc analyses from larger
trials. However, due to excellent tolerability, this treatment may be
preferred in the elderly, particularly in patients with allodynia and
small area of pain. Despite established efficacy, strong opioids should
be recommended as second choice (see the \"Potential Harms\" field).
Drugs with weak efficacy or inefficacy include mexiletine, lorazepam,
and N-methyl-D-aspartate receptor (NMDA) antagonists (**level A**).

**Trigeminal Neuralgia**

The two most widely used drugs in idiopathic trigeminal neuralgia (TN)
are CBZ (200 to 1200 mg/day) (**level A**) and OXC (600 to 1800 mg/day)
(**level B**). OXC has a lower strength of evidence than CBZ, but poses
less safety concerns. Baclofen and LTG have only **level C evidence**.
The Task Force recommends CBZ or OXC as first line. Because TN typically
lasts forever with periods of partial or complete remission and
recurrence, the patients should be taught to adapt the dosage to the
frequency of attacks. There is no evidence that combination therapies
are advantageous. In patients non-responsive to medical treatment,
surgical interventions have given excellent results. In fact, many
patients cannot withstand several weeks of pharmacological testing and
need prompt neurosurgical attention. Baclofen or LTG may be proposed as
add on in patients refractory to CBZ or OXC, particularly if the patient
cannot undergo or refuses surgery.

The task Force encourages controlled studies in symptomatic TN.

**Central Pain**

Considering the small number of randomised controlled trials (RCTs) in
central pain (CP) and the generally small sample sizes, the treatment
may be based on general principles for peripheral neuropathic pain
treatment and for side-effect profile. There is **level B** evidence for
the use of LTG, GBP, pregabalin (unpublished study) or tricyclic
antidepressants for post-stroke or spinal cord injury (SCI) pain. The
level of evidence is lower for opioids in the lack of placebo-controlled
studies (**level C**). There is **level B evidence** for inefficacy of
valproate and mexiletine in SCI pain. In CP associated with multiple
sclerosis (MS), cannabinoids have shown significant efficacy (**level
A**), but may raise safety concerns (see the \"Potential Harms\" field).
Therefore, the Task Force recommends initially a trial with other drugs
found effective on other CP conditions.

**Less Studied Neuropathic Pain Conditions**

Several less studied neuropathic conditions, such as phantom limb pain,
post-surgical neuropathic pain, and Guillain--Barre syndrome, appear to
be similarly responsive to most current drugs used in other neuropathic
conditions (e.g. TCAs, GBP, opioids), but results are based on a limited
number of generally **class II** RCTs with small sample sizes (**level
B**). Neuropathic pain due to cancer infiltration seems to be more
refractory to drug treatment, probably because it is a progressive
condition.

**Final Recommendations and Issues of Future Trials**

Selecting a first-line medication in neuropathic pain should take into
account not only the relative efficacy based at best on direct drug
comparisons, but also the ratio efficacy/safety. The effect on different
pain symptoms, comorbidities and quality of life should also be
documented. So far, such assessment has been performed in a small number
of studies for a few drugs only, and the evaluation of symptoms and
signs used sometimes inadequate or non-validated methods.

The effects of drugs on distinct peripheral neuropathic conditions share
many similarities, with the exceptions of HIV-polyneuropathy and TN.
Central pain has been much less studied. For this reason, the following
recommendations concern mainly peripheral neuropathic pain.
Recommendations pertaining to other conditions can be found in the above
sections and Table below.

Drugs with best established efficacy in various neuropathic conditions
and recommended as first line include TCA, GBP and pregabalin (**level
A, several class I trials**). TCA seem to be more efficacious on the
basis of NNT, but these values may have been overestimated and their
superiority has generally not been confirmed by substantial head-to-head
comparative trials. These drugs have cardiac effects and should be used
cautiously in elderly patients. Drugs with less established efficacy in
various neuropathic conditions and recommended as second line include
topical lidocaine, the SNRI venlafaxine and duloxetine, LTG and
tramadol. However, topical lidocaine may be preferred in patients with
PHN or focal neuropathy and small area of pain, particularly in the
elderly. Contrary to common notion about their poor efficacy in
neuropathic pain, opioids have been found efficacious in several class I
trials in various neuropathic conditions (**level A**) but should only
be proposed second to third line in chronic non-cancer pain. There is
insufficient support for the use of CBZ and OXC (with the noteworthy
exception of TN), capsaicin (with the exception of PHN), mexiletine,
NMDA antagonists, SSRI, topiramate, because of weak efficacy, discrepant
results or safety concerns. Despite long-term use of valproate for
epilepsy, RCTs have only recently appeared with this drug in peripheral
neuropathic pain with good efficacy in several class II studies from the
same group, but negative results from another group. This drug needs
further trials by other groups before its level of recommendation is
settled.

Regarding comorbidities or quality of life, only GBP, pregabalin and
duloxetine have been adequately studied with positive effects, and may
therefore be preferred in patients with severe impact of pain on quality
of life or significant comorbidities (**level A**), whilst lack of
effects of opioids on these outcomes have been reported in most trials.
Regarding pain symptoms or signs, only antidepressants and
opioids/tramadol have so far been shown effective on ongoing and
paroxysmal pain, whilst effects on brush-induced allodynia have been
reported for topical lidocaine and opioids/tramadol (**level B**). The
use of topical lidocaine may be preferred in patients with mechanical
allodynia.

Combination therapy may be proposed in cases of insufficient efficacy
with monotherapy and should preferably use drugs with complementary
mechanisms of action. It has been shown useful so far for GBP/morphine
(**level A**).

**Table Classification of Evidence for Drug Treatments in Painful
Polyneuropathy (PPN), Postherpetic Neuralgia (PHN), Trigeminal Neuralgia
(TN), and Central Pain, with Recommendations for First- and Second-line
Treatments**

  ----------------------------------------------------------------------------------------------------------
  **Pain        **Level A     **Level B         **Level C Rating or  **Recommendations   **Recommendations
  Condition**   Rating**      Rating**          Weak/Discrepant      for First Line**    for Second or Third
                                                Results with Level                       Line**
                                                A/B Evidence**                           
  ------------- ------------- ----------------- -------------------- ------------------- -------------------
  **PPN**       Gabapentin\   Lamotrigine       Capsaicin, topical\  Gabapentin\         Lamotrigine\
                Opioids^1^\                     CBZ\                 Pregabalin\         Opioids\
                Pregabalin\                     Levodopa\            TCA                 SNRI\
                SNRI\                           Mexiletine\                              Tramadol
                TCA\                            NMDA antagonists\                        
                Tramadol                        OXC\                                     
                                                SSRI^2^\                                 
                                                Topiramate\                              
                                                Valproate                                

  **PHN**       Gabapentin\   Capsaicin,        NMDA antagonists\    Gabapentin\         Capsaicin\
                Opioids^3^\   topical\          Lorazepam\           Pregabalin\         Opioids\
                Pregabalin\   Lidocaine,        Mexiletine           Lidocaine, topical  Tramadol\
                TCA           topical\                               (in patients with   Valproate
                              Tramadol\                              small area of pain- 
                              Valproate                              allodynia)\         
                                                                     TCA                 

  **TN**        CBZ           OXC               Baclofen\            OXC\                Surgery
                                                Lamotrigine          CBZ                 

  **Central                   Cannabinoids^4^   Mexiletine\          Amitriptyline\      Cannabinoids^4^\
  pain**                      (in MS)\          Opioids^6^ (in       Gabapentin\         Lamotrigine\
                              Gabapentin (in    multiple-aetiology   Pregabalin          Opioids
                              SCI)\             pains)\                                  
                              Pregabalin^5^ (in Valproate                                
                              SCI)\                                                      
                              Amitriptyline (in                                          
                              CPSP)\                                                     
                              Lamotrigine (in                                            
                              CPSP)                                                      
  ----------------------------------------------------------------------------------------------------------

Recommendations take into account not only the efficacy assessed in
class I or II trials, but also the side-effect profile and safety issues
(drugs appear in alphabetical order).

TCA have level A evidence for efficacy but should be used cautiously in
elderly patients particularly with cardiac risks. Opioids (level A
evidence for use in several neuropathic pain conditions) are recommended
second/third line because of potential safety concerns in chronic
neuropathic noncancer pain, particularly for long-term use \[111\]. SNRI
(duloxetine and venlafaxine, level A in PPN) are recommended second line
because of a comparatively lower efficacy, but may be preferred to TCA
particularly in patients with cardiovascular risk factors. Lidocaine
patches (level B evidence) may be proposed first line in patients with
small area of pain and allodynia, particularly in the elderly, because
of excellent tolerability. Lamotrigine, due to potentially severe
cutaneous rashes, is recommended second/third line. Oxcarbazepine (OXC,
level B evidence) is proposed first line in trigeminal neuralgia,
because of lower safety concerns than for carbamazepine (CBZ). Very few
trials have been performed in central pain and recommendations are
generally based on level B evidence for most treatments.

1.  Oxycodone

2.  On the basis of one RCT each, paroxetine has been found moderately
    effective and citalopram and fluoxetine ineffective.

3.  Oxycodone, morphine and methadone

4.  Cannabinoids, due to potential safety concerns, should be used after
    a negative trial with other drugs found beneficial in other central
    pain conditions.

5.  Pregabalin has been studied in a still unpublished trial in SCI.

6.  Levorphanol (controlled study, but no placebo group)

**Abbreviations**

CBZ, carbamazepine; Complex Regional Pain Syndrome (CRPS); MS, multiple
sclerosis; NMDA, N-methyl-D-aspartate receptors; OXC, oxcarbazepine;
PHN, postherpetic neuralgia; PPN, painful polyneuropathy; SCI, spinal
cord injury; SNRI, serotonin-noradrenaline reuptake inhibitor; SSRI,
selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant;
TN, trigeminal neuralgia

**[Definitions]{.underline}**:

**Evidence Classification Scheme for a Therapeutic Intervention**

**Class I**: An adequately powered prospective, randomized, controlled
clinical trial with masked outcome assessment in a representative
population or an adequately powered systematic review of prospective
randomized controlled clinical trials with masked outcome assessment in
representative populations. The following are required:

a.  Randomization concealment

b.  Primary outcome(s) is/are clearly defined

c.  Exclusion/inclusion criteria are clearly defined

d.  Adequate accounting for dropouts and crossovers with numbers
    sufficiently low to have minimal potential for bias

e.  Relevant baseline characteristics are presented and substantially
    equivalent among treatment groups or there is appropriate
    statistical adjustment for differences

**Class II**: Prospective matched-group cohort study in a representative
population with masked outcome assessment that meets a--e above or a
randomized, controlled trial in a representative population that lacks
one criteria a--e

**Class III**: All other controlled trials (including well-defined
natural history controls or patients serving as own controls) in a
representative population, where outcome assessment is independent of
patient treatment

**Class IV**: Evidence from uncontrolled studies, case series, case
reports, or expert opinion

**Rating of Recommendations**

**Level A rating** (established as effective, ineffective, or harmful)
requires at least one convincing class I study or at least two
consistent, convincing class II studies.

**Level B rating** (probably effective, ineffective, or harmful)
requires at least one convincing class II study or overwhelming class
III evidence.

**Level C rating** (possibly effective, ineffective, or harmful)
requires at least two convincing class III studies.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for selected
recommendations (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Appropriate pharmacological treatment of neuropathic pain

#### POTENTIAL HARMS

**Adverse Effects of Medications**

-   The most common side-effects of tricyclic antidepressants (TCA) are
    dry mouth, constipation, sweating, dizziness, disturbed vision,
    drowsiness, palpitation, orthostatic hypotension, sedation and
    urinary hesitation. More selective TCA such as nortriptyline are
    better tolerated than the non-selective ones, with less
    anticholinergic effects and sedation. A suspected association
    between TCA treatment and sudden cardiac death has raised concern; a
    recent epidemiological study found a slight increase in sudden
    cardiac death with TCA doses superior to 100 mg/day. Therefore
    caution is recommended for older patients, particularly those with
    cardiovascular risk factors.

-   Serotonin-noradrenaline reuptake inhibitors (duloxetine,
    venlafaxine) are safer to use than TCAs and are a better option in
    patients with cardiac disease. The relative risk for withdrawal due
    to side-effects is weak and there is no need for drug level
    monitoring. The most frequently observed adverse events with
    duloxetine are nausea, vomiting, constipation, somnolence, dry
    mouth, increased sweating, loss of appetite and weakness. Although
    immediate release venlafaxine is associated with adverse central
    nervous system (CNS) and somatic symptoms such as agitation,
    diarrhoea, increased liver enzymes, hypertension and hyponatremia
    the extended release formulation seems to be far more tolerable, the
    main side-effects being gastrointestinal disturbances

-   Carbamazepine (CBZ) entails frequent adverse events, which include
    sedation, dizziness, gait abnormalities. Liver enzymes, blood cells,
    platelets and sodium levels must be monitored for at least during 1
    year, because of possible risk for hepatitis-anaplastic effects or
    hyponatremia. Induction of microsomal enzyme systems may influence
    the metabolism of several drugs. In contrast to CBZ, oxcarbazepine
    (OXC) does not entail enzymatic induction and there is little risk
    for crossed cutaneous allergy. In the first months of treatment,
    sodium levels must be monitored because OXC, like CBZ induces
    hyponatraemia, particularly in the elderly (6% in a cohort of 54
    patients). As regards other side-effects, although a better
    tolerance has been claimed with OXC compared with CBZ, this notion
    lacks consistent evidence from class I trials. In a recent trial in
    diabetic painful polyneuropathy, 27.5% of the OXC group discontinued
    treatment due to central or gastrointestinal side-effects versus 8%
    with the placebo.

-   The most common side-effects of gabapentin (GBP) and pregabalin
    include dizziness, somnolence, peripheral oedema, and dry mouth,
    with a similar frequency for both drugs. Whilst GBP is widely
    accepted as highly tolerable even at high dosages (\>2400 mg), the
    reports on pregabalin change remarkably with the daily dose: with
    150 to 300 mg there is almost no difference with placebo, whilst the
    withdrawal rate reaches 20% with 600 mg.

-   Lamotrigine is generally well tolerated. Side-effects include
    dizziness, nausea, headache and fatigue. However, it may induce
    potentially severe allergic skin reactions. Lamotrigine should not
    be used in combination with valproate.

-   The most common side-effects of opioids are constipation, sedation,
    nausea, dizziness and vomiting. The risk of cognitive impairment has
    been reported to be negligible, although morphine may impair
    attention at very high dosages. Tramadol has been reported to induce
    dizziness, dry mouth, nausea, constipation and somnolence with
    significantly more dropouts compared with placebo. There is an
    increased risk of seizures in patients with a history of epilepsy or
    receiving drugs which may reduce the seizure threshold. Serotonergic
    syndrome (various combinations of myoclonus, rigidity,
    hyperreflexia, shivering, confusion, agitation, restlessness, coma,
    autonomic instability, fever, nausea, diarrhoea, flushing, and
    rarely, rhabdomyolysis and death) may occur if tramadol is used as
    an add-on treatment to other serotonergic medications (particularly
    selective serotonin reuptake inhibitors \[SSRIs\]).

-   The use of lidocaine patches is very safe with a very low systemic
    absorption and only local adverse effects (mild skin reactions).

-   Cannabinoids have been found generally well tolerated with low
    dosages and slow titration. Adverse events are mainly dizziness, dry
    mouth, and sedation. One study found significant memory impairment
    with cannabinoids in spray. The potential risk of physical
    dependence and tolerance warrants consideration with long-term use.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   This guideline provides the view of an expert task force appointed
    by the Scientific Committee of the European Federation of
    Neurological Societies (EFNS). It represents a peer-reviewed
    statement of minimum desirable standards for the guidance of
    practice based on the best available evidence. It is not intended to
    have legally binding implications in individual cases.

-   Although well-conducted meta-analyses or systematic reviews on
    medical treatment of neuropathic pain have been recently published,
    there is still a lack of expert consensus on guidelines regarding
    the medical treatment of neuropathic pain. This may be mainly due to
    the heterogeneity of such pain in terms of aetiologies, symptoms,
    signs, and underlying mechanisms.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

The European Federation of Neurological Societies has a mailing list and
all guideline papers go to national societies, national ministries of
health, World Health Organisation, European Union, and a number of other
destinations. Corporate support is recruited to buy large numbers of
reprints of the guideline papers and permission is given to sponsoring
companies to distribute the guideline papers from their commercial
channels, provided there is no advertising attached.

#### IMPLEMENTATION TOOLS

Staff Training/Competency Material

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio
C, Sindrup S, Wiffen P, EFNS Task Force. EFNS guidelines on
pharmacological treatment of neuropathic pain. Eur J Neurol 2006
Nov;13(11):1153-69. \[147 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17038030)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2006 Nov

#### GUIDELINE DEVELOPER(S)

European Federation of Neurological Societies - Medical Specialty
Society

#### SOURCE(S) OF FUNDING

European Federation of Neurological Societies

#### GUIDELINE COMMITTEE

European Federation of Neurological Societies Task Force on the
Pharmacological Treatment of Neuropathic Pain

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Task Force Members*: N. Attal, EFNS Panel Neuropathic Pain, INSERM
U-792, Centre d\'Evaluation et de Traitement de la Douleur, Hôpital
Ambroise Paré, AP-HP and Université Versailles-Saint-Quentin,
Boulogne-Billancourt, France; G. Cruccu, EFNS Panel Neuropathic Pain,
Department of Neurological Sciences, La Sapienza University, Rome,
Italy; M. Haanpää, EFNS Panel Neuropathic Pain, Departments of
Anaesthesiology and Neurosurgery, Pain Clinic, Helsinki University
Hospital, Helsinki, Finland; P. Hansson, EFNS Panel Neuropathic Pain,
Department of Molecular Medicine and Surgery, Section of Clinical Pain
Research and Pain Center, Department of Neurosurgery, Karolinska
Institute, University Hospital, Stockholm, Sweden; T. S. Jensen, EFNS
Panel Neuropathic Pain, Department of Neurology and Danish Pain Research
Center, Aarhus University Hospital, Aarhus, Denmark; T. Nurmikko, Pain
Research Institute, Division of Neurological Science, School of Clinical
Sciences, University of Liverpool, Liverpool, UK; C. Sampaio, Instituto
de Farmacologia e Terapeutica Geral, Lisbon School of Medicine,
University of Lisbon, Lisbon, Portugal; S. Sindrup, Department of
Neurology, Odense University Hospital, Odense, Denmark; P. Wiffen,
Cochrane Pain & Palliative Care Review Group, Oxford, UK

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The following authors (initials) did trials or have been consultant for
the following pharmaceutical companies:

NA: GlaxoSmithKline, Grunenthal, Novartis, Pfizer, Pierre Fabre,
Sanofi-Aventis

GC: GlaxoSmithKline, Lundbeck, Janssen, Novartis, Pfizer

MH: Janssen-Cilag, Merck, Mundipharma, Organon, Orion, Pfizer, Sanofi

PH: Bioschwartz, GlaxoSmithKline, Lundbeck, Pfizer

TSJ: Eli Lilly, GlaxoSmithKline, Grunenthal, Lundbeck, Neurosearch,
Pfizer

TN: Allergan, Astra-Zeneca, GlaxoSmithKline, GWPharma, Napp, Novartis,
Pfizer, Renovis, SchwarzPharma

SS: Eli Lilly, GlaxoSmithKline, Grunenthal, Lundbeck, Novartis, Pierre
Fabre, UCB Pharma

The authors have no other conflicts to declare.

#### GUIDELINE STATUS

This is the current release of the guideline.

The European Federation of Neurological Societies (EFNS) Task Force
plans to update these guidelines in 2 years.

#### GUIDELINE AVAILABILITY

Electronic copies: Available to registered users from the [European
Federation of Neurological Societies Web
site](http://www.efns.org/content.php?pid=142).

Print copies: Available from N. Attal, Centre d\'Evauation et de
Traitement de la Douleur Hôpital Ambroise Paré, Boulogne-Billancourt,
France; Telephone: 33 149 09 4434; Fax: 33 149 09 4435; e-mail:
<nadine.attal@apr.ap-hop-paris.fr>

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Brainin M, Barnes M, Baron JC, Gilhus NE, Hughes R, Selmaj K,
    Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific
    Committee. Guidance for the preparation of neurological management
    guidelines by EFNS scientific task forces -- revised
    recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81.
    Electronic copies: Available in Portable Document Format (PDF) from
    the [European Federation of Neurological Societies Web
    site](http://www.efns.org/files/guideline_23.pdf).

-   Guideline papers. European Federation of Neurological Societies.
    Electronic copies: Available from the [European Federation of
    Neurological Societies Web
    site](http://www.efns.org/content.php?pid=141).

-   Continuing Medical Education questions available from the [European
    Journal of Neurology Web
    site](http://www.blackwellpublishing.com/products/journals/ene/mcqs/).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on April 12, 2007. The
information was verified by the guideline developer on May 15, 2007.
This summary was updated by ECRI Institute on November 9, 2007,
following the U.S. Food and Drug Administration advisory on
Antidepressant drugs. This summary was updated by ECRI Institute on
January 10, 2008, following the U.S. Food and Drug Administration
advisory on Carbamazepine.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the Blackwell-Synergy copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

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approve, or endorse the guidelines represented on this site.

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Guidelines represented on the NGC Web site are submitted by guideline
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Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

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Date Modified: 11/3/2008