EFNS guidelines on pharmacological treatment of neuropathic pain

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1154 N. Attal et al.The objectives of our Task Force were: (1) to examineall the RCTs performed in the various neuropathicpain conditions; (2) to evaluate the drug effects on painsymptoms, quality of life, and sleep, and the adverseevents; (3) to propose recommendations based on theresults of these trials aiming at helping clinicians in theirtreatment choice for most neuropathic pain conditions;(4) to propose new studies that may help clarify unsolvedissues.MethodsWe conducted an initial search through the centraldatabase in the Cochrane Library. Whenever theCochrane search failed to find top level studies for agiven neuropathic pain condition or a drug which wassupposedly active on neuropathic pain, we expanded thesearch using Medline and other electronic databases(1966–to date), and checking reference lists published inmeta-analyses, review articles, and other clinical reports.Furthermore, to get the most updated information, wealso asked all the pharmaceutical companies producingdrugs in this field to provide us with studies not yetpublished (Appendix A). Any reports retrieved fromthese contacts were pooled with the others for selection.In order to provide the neurologist with clear indicationsregarding drug treatment for the most studiedneuropathic pains, the Task Force decided to produceindividual chapters for painful polyneuropathies, PHN,TN, and CP [spinal cord injury (SCI), post-stroke painand multiple sclerosis (MS)], but to search and reportalso for the other less studied neuropathic conditions(post-traumatic/post-surgical nerve lesions, phantomlimb pain, Guillain–Barre´ syndrome) and for neuropathicpains with multiple aetiology. Each chapter wasassigned to two Task Force participants.least 1 week; (6) treatment feasible in an outpatient setting(i.v., subcutaneous, or intrathecal therapy or nerveblocks were not considered); (7) evaluating currentlyused drugs or drugs under clinical phase-III development:(8) including patients with pain secondary to adefinite nervous system lesion/disease [13] or idiopathicTN; (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 nervelesion, such as atypical facial pain, CRPS type I or lowback pain, non-validated or unconventional outcomemeasures, non-pharmacological intervention, treatmentsacting directly on the disease or pre-emptive treatments.Information selected from the trialsFrom articles meeting our search criteria, we extractedinformation regarding the efficacy not only onoverall pain and main side-effects, but also effects onpain symptoms or signs, quality of life and mood,whenever available. We also referred to recent wellconductedmeta-analyses when analysis of thesestudies did not provide with additional informationregarding these end-points. We used the NNT (thenumber of patients needed to treat to obtain oneresponder to the active drug) with 95% confidenceintervals (CI) for class I/II studies in order to gaininformation regarding the overall efficacy of a drug.Unless otherwise specified, we used the NNT for 50%pain relief. These values were calculated for newertrials or extracted from recent meta-analyses performedby members of this Task Force [2,9,14] or theCochrane database [11,15–17]. We did not use theNumber Needed to Harm because of lack of uniformcriteria for assessing harmful events [2].Classification of evidenceClassification of evidence and recommendation gradingadhered to the <strong>EFNS</strong> standards [12]. In particular, classI refers not only to adequate prospective RCTs, butalso to adequately powered SR.Inclusion and exclusion criteriaIncluded studies complied with the following criteria: (1)randomized or non-randomized but controlled class I orII trials (lower-class studies were evaluated in conditionsin which no higher-level studies were available); (2) painrelief considered as a primary outcome and measuredwith validated scales; (3) minimum sample of 10 patients;(4) treatment duration and follow up clearly specified;(5) treatment assessed in repeated dose settings for atResultsPainful polyneuropathyPainful polyneuropathy (PPN) is a common neuropathicpain condition. Diabetic polyneuropathy is themost classical example. Patients usually present withspontaneous and stimulus-evoked pains with a distaland symmetrical distribution [18]. Although one ormore of the pain symptoms characteristics of neuropathicconditions are seen in the majority of the patients,the most frequent single pain symptom is deepaching pain [18]. Diabetic and non-diabetic PPN aresimilar in symptomatology and with respect to treatmentresponse [class I SR: 19]. The only exceptionsseem to concern HIV- and chemotherapy-inducedneuropathy which are described separately.Ó 2006 <strong>EFNS</strong> European Journal of Neurology 13, 1153–1169
Pharmacological treatment of neuropathic pain 1155AntidepressantsAntidepressants have recently been reviewed in twoclass I meta-analyses in neuropathic pain includingPPN [11,14]. Evidence for the efficacy of tricyclic antidepressants(TCA: amitriptyline, clomipramine, desipramine,imipramine, Table 1) has compiled sincethey were first introduced in PPN about 30 years ago.Most data stem from relatively small cross-over class Ior II trials, which may overestimate efficacy. The NNTfor TCA in painful polyneuropathy is 2.1 (CI 1.8–2.6)for drugs with balanced serotonin and noradrenalinreuptake inhibition and 2.5 (CI 1.9–3.6) for drugs thatmainly inhibit noradrenaline reuptake [14]. In one trial,amitriptyline was slightly but significantly more effectivethan maprotiline [class I: 20] whereas another trialfailed to observe significant differences betweenclomipramine and desipramine [class I: 21].Selective serotonin reuptake inhibitors (SSRI) ormianserin cause minor and clinically insufficient painrelief in four class I trials [class I SR: 11,14], whereasserotonin-noradrenaline reuptake inhibitors (SNRI)such as venlafaxine (150–225 mg/day) [class I: 22,23]and duloxetine (60–120 mg/day) [class I: 24,25] areeffective, although their effects appear generallymoderate. In a head-to-head comparative study of 33patients, venlafaxine was less effective than imipramineon the proportion of responders [class I: 23]. Withadequate dosing, the NNT is 4.6 (CI 2.9–10.6) forvenlafaxine (150–225 mg/day) and 5.2 (CI 3.7–8.5) forduloxetine (60–120 mg/day).AntiepilepticsTwo small crossover double-blind trials, publishedsome 30 years ago, reported significant effects of carbamazepine(CBZ) in diabetic PPN, but their methodsand reporting do not live up to current standards [classIII: 26,27]. One small double-blind study (n ¼16) reported similar efficacy of CBZ and nortriptylinefluphenazine,but the small sample size might preventshowing a difference [class II: 28].Oxcarbazepine (OXC) data were equivocal in PPN asjudged by abstracts from the <strong>EFNS</strong> congress in 2004,with several still unpublished negative trials. However,in a recent double-blind parallel-group placebo trial of16-week duration, OXC (300–1800 mg/day) had amodest although significant efficacy in diabetic PPNwith NNT ¼ 5.9 (CI 3.2–42.2) [class II: 29].Lamotrigine (LTG) has shown significant efficacywith NNT ¼ 4.0 (CI 2.1–42) in diabetic PPN [class I:30].Topiramate failed to relieve diabetic PPN in threelarge controlled trials [class I SR: 31] and one laterstudy found a marginal effect with NNT ¼ 7.4 (4.3–28.5) [class I: 32].Because data about valproate are controversial, withtwo very positive studies from the same groupTable 1 Predominant mechanism of actionof main drugsDrugPredominant mechanismAmitriptylineTCA, balanced monoamine reuptake inhibitionCapsaicin (topical) Depolarizes the nervous membrane via vanilloid receptor type 1,initially stimulates then blocks skin nerve fibresCarbamazepineVoltage-gated sodium-channel blockClomipramineTCA, balanced monoamine reuptake inhibitionDesipramineTCA, predominantly noradrenaline reuptake inhibitionDextromethorphan NMDA-receptor antagonistDuloxetineSNRI, serotonin-noradrenaline reuptake inhibitionGabapentinBinding to the a 2d subunit of presynaptic voltage-dependentcalcium channels with reduced release of presynaptic transmittersImipramineTCA, balanced monoamine reuptake inhibitionLidocaine (topical) Block of peripheral sodium channels and thus of ectopic dischargesLamotriginePresynaptic voltage-gated sodium-channel inhibition and thusreduced release of presynaptic transmittersMemantineNMDA-receptor antagonistNortriptylinePredominantly noradrenalin reuptake inhibitionOxcarbazepineVoltage-gated sodium- and calcium-channel blockOxycodonel-opioid-receptor agonistPregabalinBinding to the a 2d subunit of presynaptic voltage-dependentcalcium channels with reduced release of presynaptic transmittersTetrahydrocannabinol Agonist to the CB1 and the CB2 subtype of cannabinoid receptorsTopiramateVoltage-gated sodium-channel block and inhibition of glutamaterelease by an action on AMPA/kainate receptorsTramadoll-opioid-receptor agonist and monoamine reuptake inhibitorValproateIncrease of GABA levels in brain and potentiation ofGABA-mediated responsesVenlafaxineSNRI, serotonin-noradrenaline reuptake inhibitionÓ 2006 <strong>EFNS</strong> European Journal of Neurology 13, 1153–1169
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