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.

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

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:

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.

None provided

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

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

2006 Nov

European Federation of Neurological Societies - Medical Specialty Society

European Federation of Neurological Societies

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

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

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.

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.

None available

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