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Guideline Summary
Guideline Title
EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.
Bibliographic Source(s)
Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010 Sep;17(9):1113-e88. [105 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

This is guideline updates the previous version: 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.

Scope

Disease/Condition(s)

Neuropathic pain, including:

  • Painful polyneuropathy (PPN)
  • Postherpetic neuralgia (PHN)
  • Trigeminal neuralgia (TN)
  • Central neuropathic pain (CP)
  • Other neuropathic pain (NP) conditions

Note: Neuropathic pain (NP) may be caused by a lesion or a disease of the somatosensory system.

Guideline Category
Assessment of Therapeutic Effectiveness
Treatment
Clinical Specialty
Family Practice
Internal Medicine
Neurology
Pharmacology
Intended Users
Advanced Practice Nurses
Nurses
Pharmacists
Physician Assistants
Physicians
Guideline Objective(s)
  • To examine all the randomized controlled trials (RCTs) performed in the various neuropathic pain (NP) conditions since 2005
  • To propose recommendations aimed at helping clinicians in their treatment choice for most NP conditions
  • To propose studies that may clarify unresolved issues
Target Population

Patients with neuropathic pain

Interventions and Practices Considered

Painful Polyneuropathy

  1. First-line treatment: gabapentin, pregabalin, tricyclic antidepressants (TCA), serotonin-norepinephrine reuptake inhibitors (SNRI) (duloxetine, venlafaxine)
  2. Second-line treatment: tramadol, tramadol/acetaminophen combination
  3. Third-line treatment: strong opioids
  4. Human immunodeficiency virus (HIV)-associated polyneuropathy: lamotrigine (in patients receiving antiretroviral treatment), smoking cannabis, and capsaicin patches

Postherpetic Neuralgia

  1. First-line treatment: TCA, gabapentin/pregabalin, lidocaine (in the elderly)
  2. Second-line treatment: strong opioids, capsaicin cream

Trigeminal Neuralgia

  1. First-line treatment: oxcarbazepine, carbamazepine
  2. Patients with intolerable side effects of first-line treatment: lamotrigine, surgery

Central Neuropathic Pain

  1. First line treatment: gabapentin, pregabalin, amitriptyline
  2. Second/third-line treatment: tramadol, strong opioids
  3. Lamotrigine (in central post-stroke pain or spinal cord injury pain with incomplete cord lesion and brush-induced allodynia) and cannabinoids (in multiple sclerosis [MS])

Note: Refer to Tables 1 and 2 in the original guideline for a list of all of the drug treatments considered, including those that were found ineffective or that are not generally recommended and those that are not yet available for use.

Major Outcomes Considered
  • Effectiveness of treatment in relieving pain and improving quality of life, sleep, and comorbidities
  • Side effects of medications

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
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 of the Cochrane Library from 2005. Whenever the Cochrane search failed to find top-level studies for a given neuropathic pain (NP) condition or a potentially effective drug, the Task Force expanded the search using Medline and other electronic databases including Web results from major unpublished company trials (January 2005–September 2009). As in the first guidelines, the Task Force produced individual chapters and guidelines based on aetiological conditions. Each chapter was assigned to two or more Task Force participants. Classification of evidence and recommendation grading adhered to the European Federation for Neurological Societies (EFNS) standards.

Inclusion criteria were the following: controlled class I or II trials (lower class studies were evaluated in conditions in which no higher level studies were available); trials including patients with probable or definite NP or trigeminal neuralgia; chronic NP (≥3 months); pain considered as the primary outcome (e.g., studies in which dysesthesia was the primary outcome, as in chemotherapy-induced neuropathy, were excluded); minimum sample of 10 patients; treatment duration and follow-up specified; treatment feasible in an outpatient setting; studies evaluating currently used drugs or drugs under clinical phase-III development: full paper citations in English.

Exclusion criteria included duplicated patient series, conditions with no evidence of lesion in the somatosensory system (e.g., complex regional pain syndrome [CRPS] I, fibromyalgia, low-back pain), studies using non-validated primary outcome measures, disease modifying treatments (i.e., alpha-lipoic acid for diabetes) and pre-emptive treatments.

Number of Source Documents

The search strategy identified 64 randomized controlled trials (RCTs) since January 2005 using placebo or active drugs as comparators and three subgroup or post hoc analyses of prior RCTs.

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:

  1. Randomization concealment
  2. Primary outcome(s) is/are clearly defined
  3. Exclusion/inclusion criteria are clearly defined
  4. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
  5. 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

The task force extracted information regarding the efficacy on pain, symptoms/signs, quality of life, sleep and mood and side effects (see Appendices 1 and 2 in the original guideline document).

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Not stated

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).

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

The Task Force recommends tricyclic antidepressants (TCA), gabapentin, pregabalin and serotonin-norepinephrine reuptake inhibitors (SNRI) (duloxetine, venlafaxine) as first-line treatment in painful polyneuropathy (PPN) (notably related to diabetes) (Level A). Tramadol (Level A) is recommended second line except for patients with exacerbations of pain (for the tramadol/acetaminophen combination) or those with predominant coexisting non-neuropathic pain (in view of its largely established efficacy in nociceptive pain). Third-line therapy includes strong opioids because of concerns regarding their long-term safety including addiction potential and misuse, which warrants further randomized controlled trials (RCTs) (Dworkin et al., 2007; Eisenberg, McNicol, & Carr, 2005). Treatments with drug with no or equivocal effect are listed in Table 1 in the original guideline document. In human immunodeficiency virus (HIV)-associated polyneuropathy, only lamotrigine (in patients receiving antiretroviral treatment) (Level B), smoking cannabis (Level A) and capsaicin patches (Level A) were found moderately useful.

Post-herpetic Neuralgia

The Task Force recommends TCA or gabapentin/pregabalin as first-line treatment in post-herpetic neuralgia (PHN) (Level A). Topical lidocaine (Level A, less consistent results) with its excellent tolerability may be considered first line in the elderly, especially if there are concerns regarding the central nervous system (CNS) side effects of oral medications. In such cases, a trial of 2–4 weeks before starting other therapy is justified (Binder et al., 2009). Strong opioids (Level A) and capsaicin cream are recommended as second choice. Capsaicin patches are promising (Level A), but the long-term effects of repeated applications particularly on sensation are not clarified.

Trigeminal Neuralgia

In agreement with previous guidelines (Attal et al., 2006; Gronseth et al., 2008; Cruccu et al., 2008), carbamazepine (Level A) and oxcarbazepine (Level B) are confirmed first line for classical trigeminal neuralgia (TN). Oxcarbazepine may be preferred because of decreased potential for drug interactions. Patients with intolerable side effects may be prescribed lamotrigine (Level C) but should also be considered for a surgical intervention. The Task Force deplores the persistent lack of RCTs in symptomatic TN.

Central Neuropathic Pain

The Task Force recommends pregabalin (Level A), amitriptyline (Level B, Level A in other neuropathic [NP] conditions) or gabapentin (Level A in other NP conditions) as first line in central neuropathic pain (CP) (see Table 1 in the original guideline document). Tramadol (Level B) may be considered second line. Strong opioids (Level B) are recommended second or third line if chronic treatment is not an issue. Lamotrigine may be considered in central post-stroke pain (CPSP) or spinal cord injury (SCI) pain with incomplete cord lesion and brush-induced allodynia (Level B) and cannabinoids in multiple sclerosis (MS) (Level A) only if all other treatments fail.

Final Recommendations

The present revised European Federation for Neurological Societies (EFNS) guidelines confirm TCA (25–150 mg/day), gabapentin (1200–3600 mg/day) and pregabalin (150–600 mg/day) as first line for various neuropathic pain (NP) conditions (except for trigeminal neuralgia) and lidocaine plasters (up to 3 plasters/day) first line in PHN particularly in the elderly. The Task Force now is able to recommend SNRI (duloxetine 60–120 mg/day, venlafaxine 150–225 mg/day) first line in painful diabetic polyneuropathies based on their more established efficacy. TCA raise safety issues at high doses and in the elderly; they are not more effective than gabapentin based on one comparative trial (Gilron et al., 2009), but they are less costly (Jensen, Chodroff, & Dworkin, 2007). Pregabalin has pharmacokinetic advantages compared to gabapentin (twice a day [bid] dosing, dose-dependent efficacy) but has similar efficacy and tolerability based on meta-analyses. Second-line treatments include tramadol (200–400 mg/day) except in select conditions and capsaicin cream in PHN. Strong opioids are recommended as second/third line despite established efficacy in neuropathic non-cancer pain because of potential risk for abuse on long-term use, as there are still too few long-term safety trials in neuropathic pain (Eisenberg, McNicol, & Carr, 2005). Capsaicin patches are promising for painful HIV neuropathies or PHN (Level A). Cannabinoids ([Level A] in MS and peripheral NP) are proposed for refractory cases. Combination therapy ([Level A] for gabapentin combined with opioids or TCA) is recommended for patients who show partial response to drugs administered alone.

Definitions:

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:

  1. Randomization concealment
  2. Primary outcome(s) is/are clearly defined
  3. Exclusion/inclusion criteria are clearly defined
  4. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
  5. 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

References 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

  • Antidepressants: Side effects are mainly gastrointestinal, but elevated blood pressure and clinically significant electrocardiogram (ECG) changes were reported in 5% of patients. Frequent adverse events of duloxetine are nausea, somnolence, dry mouth, constipation, diarrhoea, hyperhidrosis and dizziness; discontinuation rates are 15–20%. Duloxetine induces no/little cardiovascular side effects, but rare cases of hepatotoxicity have been reported.
  • Antiepileptics: Side effects include dizziness, somnolence, peripheral oedema, weight gain, asthenia, headache and dry mouth. In a recent comparative trial, only two side effects differentiated gabapentin and nortriptyline: dry mouth (more frequent with nortriptyline) and concentration disorders (more frequent with gabapentin). Discontinuation rates for pregabalin range from 0 (150 mg/day) to 20% (600 mg/day).
  • Opioids: Side effects include mainly nausea and constipation, but long-term use of opioids may be associated with misuse (2.6% in a recent 3-year registry study of oxycodone in mainly diabetic neuropathic pain, although higher rates were also reported). Tramadol should be used with caution in elderly patients because of risk of confusion and is not recommended with drugs acting on serotonin reuptake such as SSRIs. There is also concern regarding the long-term safety of opioids, including addiction potential and misuse.
  • Topical agents: Lidocaine plasters may have local adverse effects (mild skin reactions). Adverse effects of capsaicin patches are primarily attributable to local capsaicin-related reactions at the application site (pain, erythema).
  • Cannabinoids: Adverse events (dizziness, dry mouth, sedation, fatigue, gastrointestinal effects, oral discomfort) were reported by 90% of patients in a long-term extension study (up to 3 years), but no tolerance was observed.

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.

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.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010 Sep;17(9):1113-e88. [105 references] PubMed External Web Site Policy
Adaptation

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

Date Released
2006 Nov (revised 2010 Sep)
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-987, Centre d'Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, APHP, Boulogne-Billancourt, and Université Versailles-Saint-Quentin, Versailles, France; G. Cruccu, EFNS Panel Neuropathic Pain, Department of Neurological Sciences, La Sapienza University, Rome, Italy; R. Baron, EFNS Panel Neuropathic Pain, Division of Neurological Pain Research and Therapy, Department of Neurology, Universitatsklinikum Schleswig-Holstein, Kiel, Germany; M. Haanpää, EFNS Panel Neuropathic Pain, Rehabilitation ORTON and Department of Neurosurgery, Helsinki University Hospital, Helsinki, Finland; P. Hansson, EFNS Panel Neuropathic Pain, Department of Molecular Medicine and Surgery, 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, EFNS Panel Neuropathic Pain, Pain Research Institute, Neuroscience Research Unit, School of Clinical Sciences, University of Liverpool, Liverpool, UK

Financial Disclosures/Conflicts of Interest

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

NA: Grunenthal, Novartis, Pfizer, Eli Lilly/Boehringer, Pierre Fabre, Sanofi-Pasteur Merieux. RB: Pfizer, Genzyme, Grunenthal, Mundipharma, Allergan, Sanofi-Pasteur, Medtronic, Eisai, UCB, Lilly. GC: Boehringer Ingelheim, Eli Lilly, Medtronic, Pfizer. MH: Boehringer Ingelheim, Janssen-Cilag, GlaxoSmithKline, EMEA, Merck, Mundipharma, Orion, Pfizer, Sanofi-Pasteur. PH: Bioschwartz, GlaxoSmithKline, Eli Lilly/Boehringer Ingelheim, Grunenthal, Lundbeck, Neurosearch, Pfizer. TSJ: Eli Lilly, GlaxoSmithKline, Grunenthal, Pierre Fabre Takeda Pfizer. TN: Allergan, AstraZeneca, GlaxoSmithKline, GWPharma, Napp, Novartis, Pfizer, Renovis, SchwarzPharma

Guideline Status

This is the current release of the guideline.

This is guideline updates the previous version: 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.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies (EFNS) Web site External Web Site Policy.

Print copies: Available from N. Attal, Centre d'Evaluation 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 is 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 (EFNS) Web site External Web Site Policy.
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. This summary was updated by ECRI Institute on March 10, 2009, following the U.S. Food and Drug Administration advisory on Topical Anesthetics. This summary was updated by ECRI Institute on May 1, 2009 following the U.S. Food and Drug Administration advisory on antiepileptic drugs. This summary was updated by ECRI Institute on January 8, 2010, following the U.S. Food and Drug Administration advisory on Valproate sodium. This summary was updated by ECRI Institute on July 20, 2010, following the U.S. Food and Drug Administration advisory on Ultram (tramadol hydrochloride), Ultracet (tramadol hydrochloride/acetaminophen). This summary was updated by ECRI Institute on September 15, 2010, following the U.S. Food and Drug Administration advisory on Lamictal (lamotrigine). This NGC summary was updated by ECRI Institute on February 10, 2011. This summary was updated by ECRI Institute on October 28, 2013 following the U.S. Food and Drug Administration advisory on Acetaminophen.

Copyright Statement

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

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