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Keywords:

  • neuropathic pain;
  • painful diabetic polyneuropathy;
  • post-herpetic neuralgia;
  • trigeminal neuralgia;
  • central neuropathic pain;
  • evidence-based recommendations;
  • pharmacological treatment;
  • randomized clinical trials

Abstract

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Methods
  5. Results
  6. Conflicts of interest
  7. References
  8. Appendices

Background and objectives:  This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005.

Methods:  Studies were identified using the Cochrane Database and Medline. Trials were classified according to the aetiological condition. All class I and II randomized controlled trials (RCTs) were assessed; lower class studies were considered only in conditions that had no top-level studies. Treatments administered using repeated or single administrations were considered, provided they are feasible in an outpatient setting.

Results:  Most large RCTs included patients with diabetic polyneuropathies and post-herpetic neuralgia, while an increasing number of smaller studies explored other conditions. Drugs generally have similar efficacy in various conditions, except in trigeminal neuralgia, chronic radiculopathy and HIV neuropathy, with level A evidence in support of tricyclic antidepressants (TCA), pregabalin, gabapentin, tramadol and opioids (in various conditions), duloxetine, venlafaxine, topical lidocaine and capsaicin patches (in restricted conditions). Combination therapy appears useful for TCA-gabapentin and gabapentin-opioids (level A).

Conclusions:  There are still too few large-scale comparative studies. For future trials, we recommend to assess comorbidities, quality of life, symptoms and signs with standardized tools and attempt to better define responder profiles to specific drug treatments.


Background and objectives

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Methods
  5. Results
  6. Conflicts of interest
  7. References
  8. Appendices

Neuropathic pain (NP) may be caused by a lesion or a disease of the somatosensory system [1] and is estimated to afflict as high as 7–8% of the general population in Europe [2,3]. The management of NP is challenging because the response to most drugs remains unpredictable [4] despite attempts to develop a more rationale therapeutic approach [5,6]. In 2006, the European Federation of Neurological Societies (EFNS) produced the first guidelines on pharmacological treatment of NP [7]. Since 2006, new randomized controlled trials (RCTs) have appeared in various NP conditions, justifying an update.

The objectives of our revised Task Force were (i) to examine all the RCTs performed in various NP conditions since 2005, (ii) to propose recommendations aiming at helping clinicians in their treatment choice for most NP conditions, and (iii) to propose studies that may clarify unresolved issues.

Methods

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Methods
  5. Results
  6. Conflicts of interest
  7. References
  8. Appendices

We conducted an initial search of the Cochrane Library from 2005. Whenever the Cochrane search failed to identify top-level study for a given NP condition or a potentially effective drug, we expanded the search to Medline and other electronic databases including Web results from major unpublished company trials (January 2005–September 2009). As in the first guidelines, we 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 EFNS standards [8].

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 [1] or trigeminal neuralgia; chronic NP (≥3 months); pain considered as the primary outcome (e.g. studies in which dysesthesia were 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. CRPS I, fibromyalgia, low-back pain), studies using non-validated primary outcome measures, disease modifying treatments (i.e., alphalipoic acid for diabetes) and pre-emptive treatments.

We extracted information regarding the efficacy on pain, symptoms/signs, quality of life, sleep and mood and side effects (see Appendices 1 and 2).

Results

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Methods
  5. Results
  6. Conflicts of interest
  7. References
  8. Appendices

Our search strategy identified 64 RCTs since January 2005 using placebo or active drugs as comparators and three subgroup or post hoc analyses of prior RCTs.

Painful polyneuropathy

Painful polyneuropathy (PPN) is a common NP condition. Diabetic and non-diabetic PPN are similar in symptomatology and with respect to treatment response, with the exception of HIV-induced neuropathy.

Antidepressants

The efficacy of tricyclic antidepressants (TCA) is largely established in PPN (notably diabetic), although mainly based on single centre class I or II trials [7,9,10]. Three RCTs reported the efficacy of venlafaxine ER in PPN, although this seems lower than imipramine on responders and quality of life in a comparative trial [7,11]. Side effects are mainly gastrointestinal, but elevated blood pressure and clinically significant ECG changes were reported in 5% of patients. The efficacy of duloxetine is established by three large-scale trials in diabetic PPN [12], with similar efficacy to that of gabapentin/pregabalin based on one industry-funded meta-analysis [13], although direct comparisons are lacking; the effect is reported to persist for one year [14]. Frequent adverse events are nausea, somnolence, dry mouth, constipation, diarrhoea, hyperhidrosis and dizziness; discontinuation rates are 15–20% [15,16]. Duloxetine induces no/little cardiovascular side effects, but rare cases of hepatotoxicity have been reported [15]. Selective serotonin reuptake inhibitor (SSRI) or mianserin provides little or no pain relief [7,17].

Antiepileptics

Gabapentin and pregabalin are effective in diabetic PPN [18,19], with dose-dependent effects for pregabalin (several negative studies for 150 mg/day, mainly positive studies for 300–600 mg/day) [19] and similar efficacy between gabapentin and the TCA nortriptyline in a recent class I study [20]. 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) [20]. Discontinuation rates for pregabalin range from 0 (150 mg/day) to 20% (600 mg/day) [19,21]. All the other trialled antiepileptics show variable and sometimes discrepant results. Smaller class III trials (carbamazepine) suggest efficacy [7], while larger placebo-controlled studies usually show no or limited benefit (Table 1) [7,22–29]. One reason for this variability could be a large placebo effect [30].

Table 1.  Classification of evidence for drug treatments in commonly studied neuropathic pain (NP) conditions and recommendations for use. Treatments are presented in alphabetical order. Only drugs used at repeated dosages are shown here (with the exception of treatments with long-lasting effects such as capsaicin patches). Drugs marked with an asterisk were found effective in single class II or III studies and are generally not recommended. Drugs marked with two asterisks are not yet available for use.
AetiologyLevel A rating for efficacyLevel B rating for efficacyLevel C rating for efficacyLevel A/B rating for inefficacy or discrepant resultsRecommendations for first lineRecommendations for second or third line
  1. aDiabetic neuropathy was the most studied. Only TCA, tramadol and venlafaxine were studied in non-diabetic neuropathies. bAmitriptyline, clomipramine (diabetic neuropathy), nortriptyline, desipramine, imipramine. cTramadol may be considered first line in patients with acute exacerbations of pain especially for the tramadol/acetaminophen combination. dLidocaine is recommended in elderly patients (see section 2). eCannabinoids (positive effects in MS) and lamotrigine (positive effects in CPSP but negative results in MS and SCI except in patients with incomplete lesion and brush-induced allodynia in one study based on post hoc analysis) are proposed for refractory cases. iont., iontophoresis; CPSP, central post-stroke pain; ER, extended release; MS, multiple sclerosis; PHN, post-herpetic neuralgia; SCI, spinal cord injury; TCA, tricyclic antidepressants; SSRI, Selective serotonin reuptake inhibitor.

Diabetic NPaDuloxetine Gabapentin-morphine TCA Gabapentin Nicotine agonist** Nitrate derivatives** Oxycodone Pregabalin TCAb Tramadol alone or with acetaminophen Venlafaxine ERBotulinum toxin* Dextromethorphan Gabapentin/venlafaxine* Levodopa*Carbamazepine PhenytoinCapsaicin cream Lacosamide Lamotrigine Memantine Mexiletine Mianserin NK1 antagonist** Oxcarbazepine SSRI Topical clonidine Topiramate Valproate ZonisamideDuloxetine Gabapentin Pregabalin TCA Venlafaxine EROpioids Tramadolc
PHNCapsaicin 8% patch** Gabapentin Gabapentin ER** Lidocaine plasters Opioids (morphine, oxycodone, methadone) Pregabalin TCAbCapsaicin cream Valproate* Benzydamide topical Dextromethorphan Fluphenazine Memantine Lorazepam Mexiletine COX-2 inhibitor** TramadolGabapentin Pregabalin TCA Lidocaine plastersdCapsaicin Opioids
Classical trigeminal neuralgiaCarbamazepineOxcarbazepineBaclofen* Lamotrigine* Pimozide* Tizanidine* Carbamazepine OxcarbazepineSurgery
Central paineCannabinoids (oro-mucosal **, oral) (MS) Pregabalin (SCI)Lamotrigine (CPSP) TCA (SCI, CPSP) Tramadol (SCI)* Opioids Carbamazepine Gabapentin Lamotrigine (SCI) Levetiracetam Mexiletine S-ketamine iont. ValproateGabapentin Pregabalin TCACannabinoids (MS) Lamotrigine Opioids Tramadol (SCI)
Opioids

Oxycodone, tramadol [31,32] and tramadol/acetaminophen combination [33] reduce pain in diabetic PPN. 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 NP, although higher rates were also reported) [4,34]. 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 [7,32]. The tramadol/acetaminophen combination appears better tolerated [33].

Others

Recent studies reported efficacy of botulinum toxin type A [35], nitrate derivatives [36,37] and a new nicotinic agonist [38]. Of the other drugs trialled in PPN, one reported a positive outcome (levodopa), another showed discrepant results (NMDA antagonists), while the rest had limited or no efficacy (Table 1) [10,39].

Combination

Three class I studies found a superiority of the gabapentin-opioids (morphine, oxycodone) and gabapentin/nortriptyline combinations compared to each drug alone in patients with diabetic PN including Post-Herpetic Neuralgia (PHN) in two studies [20,40,41], while a small study suggested superiority of the gabapentin/venlafaxine combination compared with gabapentin and placebo [7].

HIV neuropathy

Most initial trials of HIV neuropathy were negative (Table 1) [7,42]. Only lamotrigine was moderately effective in patients receiving antiretroviral treatment [43]. Recent RCTs found efficacy of smoked cannabis (1–8% tetrahydrocannabinol for 5 days) on pain intensity but not mood or functioning [44,45]. A one-off application of high concentration (8%) capsaicin patch applied to the feet for 30, 60 or 90 min was superior to low concentration (0.04%) in the 30- and 90-minute group from weeks 2 to 12 without detectable changes in sensory thresholds [46]. However, another study reported in a systematic review [47] was negative on the primary outcome.

Recommendation.  We recommend TCA, gabapentin, pregabalin and SNRI (duloxetine, venlafaxine) as first-line treatment in 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 RCTs [4,48]. Treatments with drug with no or equivocal effect are listed in Table 1. In 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

Post-herpetic neuralgia is a common aftermath of herpes zoster in the elderly.

Antidepressants

Systematic reviews concur that TCA are effective in PHN [9,49] with superiority over SSRI [7,50]. No studies were found on the efficacy of SNRI.

Antiepileptics

Gabapentin and pregabalin have established efficacy in PHN with no difference shown between gabapentin and nortriptyline in a further comparative study [20,49] An extended release formulation of gabapentin was more effective than placebo [51]. Good efficacy was reported with divalproex sodium in a small RCT, but only results from completers were reported [52].

Opioids

Oxycodone, morphine and methadone are effective in PHN [49] and have similar or slightly better efficacy compared to TCA in one comparative trial but are associated with more frequent discontinuation due to side effects [7,49]. Tramadol was negative on the primary outcome in one class I trial [7].

Topical agents

Lidocaine plasters (5%) are effective based on 5 class I or II RCTs in PHN with brush-induced allodynia, but the therapeutic gain is modest against placebo, and the level of evidence is lower than for systemic agents [7,53]. The largest recent trial including patients with or without allodynia (with enriched enrolment design) was negative on the primary outcome (time-to-exit), but the groups were not balanced at baseline, and many patients withdrew prematurely from the study [54]. In an enriched-design open-label trial, lidocaine plaster was better tolerated than pregabalin [55]. Lidocaine plasters are safe because of their low systemic absorption and well tolerated with local adverse effects only (mild skin reactions) [54–56].

Randomized controlled trials have reported benefit from topical capsaicin 0.075% [7], but as a result of the burning effect of capsaicin, blinding was probably compromised. A one-off application of high concentration (8%) capsaicin patch applied to the skin for 60 min was more effective than a low concentration patch (0.04%) during 12 weeks [57]. Although a post hoc analysis suggests that blinding was successful, patient randomized to the high concentration patch required more rescue medication immediately after application. Adverse effects were primarily attributable to local capsaicin-related reactions at the application site (pain, erythema). Efficacy of capsaicin patches was demonstrated in two other studies reported in a systematic review [47].

Others

NMDA antagonists, lorazepam and a selective Cox2 inhibitor do not provide pain relief in PHN (Table 1) [7,58].

Recommendation

We recommend TCA or gabapentin/pregabalin as first-line treatment in 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 CNS side effects of oral medications. In such cases, a trial of 2–4 weeks before starting other therapy is justified [54]. Strong opioids (level A) and capsaicin cream are recommended as second choice (see section 1). Capsaicin patches are promising (level A), but the long-term effects of repeated applications particularly on sensation are not clarified.

Trigeminal neuralgia

Trigeminal neuralgia (TN) typically presents with very brief attacks of pain (electric shocks) and is divided into ‘classic’ when secondary to vascular compression of the trigeminal nerve in the cerebellopontine angle or when no cause is found, or ‘symptomatic’ when secondary in particular to cerebellopontine angle masses or multiple sclerosis [59].

Carbamazepine, oxcarbazepine

Carbamazepine is the drug of choice in TN, but its efficacy may be compromised by poor tolerability and pharmacokinetic interactions. Two class II RCTs found similar effects of oxcarbazepine compared to carbamazepine on the number of attacks and global assessment [60,61].

Others

Several drugs (i.e., lamotrigine, baclofen) have been reported efficacious in TN based on small single trials each [61,62] (Table 1), but a Cochrane review [63] concludes that there is insufficient evidence to recommend them in TN. Small open-label studies also suggested therapeutic benefit from botulinum toxin A and some antiepileptics [62,64,65] (Table 1).

Symptomatic TN

There are only small open-label class IV studies in symptomatic TN associated with multiple sclerosis [62].

Recommendation

In agreement with previous guidelines [7,61,62], carbamazepine (level A) and oxcarbazepine (level B) are confirmed first line for classical 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. We deplore the persistent lack of RCTs in symptomatic TN.

Central neuropathic pain

The most frequent central neuropathic pain (CP) states are caused by stroke (central post-stroke pain, CPSP), spinal cord injury (SCI) or multiple sclerosis (MS).

Antidepressants

The beneficial effects of TCA were suggested in CPSP, but one large-scale study was negative in SCI pain probably because of low doses and lack of specific evaluation of NP [7,66]. A recent RCT in SCI pain showed that high doses of amitriptyline (150 mg/day) relieved pain more effectively than diphenhydramine and gabapentin (3600 mg) in depressed patients [67]. Despite its limitations (small study, high dose of amitriptyline), it suggests that TCA can justifiably be considered for SCI patients particularly those with depression. No RCT has evaluated the efficacy of SNRI in CP.

Antiepileptics

The efficacy of pregabalin was demonstrated in a multicentre study of traumatic SCI pain [68] and confirmed in various CP conditions in a single centre study [20,69]. Discrepant results were reported with gabapentin and lamotrigine [7,43,67,70]. Negative results were obtained with other antiepileptics (Table 1) [7,71].

Opioids

Evidence for efficacy of opioids in CP is based on only one study comparing high and low doses of levorphanol in which patients with peripheral or central NP participated [72]. A recent RCT showed beneficial effect of tramadol on pain intensity, but not pain affect but many side effects were observed and caused attrition in 43% of cases (17% for the placebo) [73].

Cannabinoids

Cannabinoids (tetrahydrocannabinol, oromucosal sprays 2.7 mg delta-9-tetrahydrocannabinol/2.5 mg cannabidiol) were effective in MS-associated pain in two class I trials [7]. Adverse events (dizziness, dry mouth, sedation, fatigue, gastrointestinal effects, oral discomfort) were reported by 90% of patients in long-term extension study (up to 3 years), but no tolerance was observed [74].

Others

Negative results were obtained with low-dose mexiletine in SCI pain and S-ketamine iontophoretic transdermal in CP [7,75].

Recommendation

We recommend pregabalin (level A), amitriptyline (level B, level A in other NP conditions) or gabapentin (level A in other NP conditions) as first line in CP (Table 1). 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 CPSP or SCI pain with incomplete cord lesion and brush-induced allodynia (level B) and cannabinoids in MS (level A) only if all other treatments fail.

Other NP conditions

The level of evidence for drugs in other NP conditions is reported in Table 2.

Table 2.  Classification of evidence for drug treatments in less commonly studied neuropathic pain (NP) conditions. Treatments are presented in alphabetical order. Drugs marked with an asterisk were found effective in single class II studies
Aetiology of NPLevel A rating for efficacyLevel B rating for efficacyLevel A/B rating for inefficacy/poor efficacy or discrepant results
  1. aThese drugs were found effective in some spontaneous NP symptoms (gabapentin) or only on brush-induced or static mechanical allodynia (mexiletine, venlafaxine) in single trials. ER, extended release; TCA, tricyclic antidepressants.

HIV neuropathyCapsaicin 8% patch Smoked cannabisLamotrigineAmitriptyline Capsaicin cream Gabapentin Lidocaine plasters Memantine
Post-traumatic or post-surgical NP Amitriptyline* Botulinum toxin-A*Cannabinoids Capsaicin Gabapentin Levetiracetam Propranolol Venlafaxine ER
Chronic radiculo-pathy  Morphine* Nortriptyline* Nortriptyline-morphine * Pregabalin (unpublished) Topiramate
Cancer NPGabapentinAmitriptyline* Tramadol*Valproate
Phantom painMorphine Tramadol Amitriptyline Gabapentin Memantine Mexiletine
Multi-aetiology NPBupropion Cannabinoids (oromucosal, synthetic analogue) LevorphanolMethadone TCA (nortriptyline, clomipramine)Amitriptyline/ketamine topical CCK2 antagonists Dextromethorphan Dihydrocodeine Gabapentina Venlafaxine ERa Lidocaine plasters Lamotrigine Lidocaine plasters Mexiletinea Nabilone Riluzole

Cancer NP:  There is level A evidence for the efficacy of gabapentin (one study), level B for TCA and tramadol and inefficacy of valproate [7,76,77]. Traumatic NP: Gabapentin was reported to be ineffective on the primary outcome in a large multicentre trial but improved several secondary outcomes and may be beneficial in a subgroup of patients (level A) although predictors of the response need to be identified [78]; antidepressants have level B evidence, good results were reported for botulinum toxin A, and discrepant or negative results were obtained with other drugs [79,80]. Radiculopathy: Pregabalin (level A), TCA and opioids and their combination (level B) are ineffective or slightly effective (the combination TCA/opioids was effective on maximal pain only in one study) [81–83]. Phantom pain: Efficacy of tramadol and morphine was reported (level A), while gabapentin induced discrepant results [84,85]. Results in multi-aetiology NP are positive mainly for antidepressants (bupropion, TCA), opioids (levorphanol, methadone) and cannabinoids [7,86–92].

Effects on pain symptoms and signs and predictors of the response

Randomized controlled trials increasingly assess symptoms and signs [60] and suggest that drugs (gabapentin, oxycodone, topical lidocaine, cannabinoids) have differential effects on the quality of NP (i.e., burning, deep, paroxysmal) [7,93,94] and that some may alleviate brush-induced and/or static mechanical allodynia based on single trials (TCA, pregabalin, cannabinoids, topical lidocaine, venlafaxine, NMDA antagonists but not lamotrigine) [7,50,87,88,95]. Although predictors of response to some drugs (e.g., opioids, lidocaine plasters) were identified in post hoc analyses [79,96,97], no RCT has yet been designed to detect predictive factors of the response based on baseline phenotypic profile (level C).

Effects on Quality of Life (QoL), sleep and mood

Quality of Life, sleep and mood are frequently impaired in patients with NP [98,99]. Generally, the effects on pain are related to improvement in QoL [100; however see 75]. Beneficial effects of duloxetine, pregabalin and gabapentin were reported on these outcomes in class I trials [7,40,99,101]. However, the most consistent effects were observed with pregabalin and gabapentin on sleep quality [40,98], and poor results were reported with pregabalin on QoL or mood in 6 trials. Three trials reported the efficacy TCA on QoL [40,99,102]. Opioids and tramadol improve pain impact on sleep but have discrepant effects on QoL [99], cannabinoids alleviate QoL or sleep [44,45,87], but these drugs generally do not improve mood [32,72,73,76,87].

Final recommendations and issues for future trials

The present revised EFNS guidelines confirm TCA (25–150 mg/day), gabapentin (1200–3600 mg/day) and pregabalin (150–600 mg/day) as first line for various NP conditions (except for trigeminal neuralgia, section 3) and lidocaine plasters (up to 3 plasters/day) first line in PHN particularly in the elderly (section 2). We now are 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 [20], but they are less costly [98]. Pregabalin has pharmacokinetic advantages compared to gabapentin (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 (section 1) 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 [48] 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.

To date, the choice between these different treatments is mainly in their ratio efficacy/safety and in the patients’ clinical condition (e.g. comorbidities, contraindications, concomitant treatments). However, in a recent study investigating more than 2000 patients with neuropathic pain caused by diabetic neuropathy and post-herpetic neuralgia, Baron and colleagues [103] found that patients with these conditions could be subgrouped according to specific sensory profiles. A classification per sensory profiles rather than based merely on aetiology could contribute to minimize pathophysiological heterogeneity within study groups and increase the positive treatment responses [104,105].

We propose the following strategy for future trials: (i) Efficacy should be based on standardized end-points [60]; in establishing such efficacy, symptoms/signs and QoL in addition to overall pain should be identified; (ii) Identification of responder profiles based on a detailed characterization of symptoms and signs using sensory examination and specific pain questionnaires should contribute to more successful neuropathic pain management; (iii) Identical criteria for assessing harmful events should be obtained; (iv) Large-scale comparative trials of drugs should be conducted; (v) More large-scale trials are needed to determine the value of combination therapy.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Methods
  5. Results
  6. Conflicts of interest
  7. References
  8. Appendices

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 Mérieux. RB: Pfizer, Genzyme, Grünenthal, 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, Sanof-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.

References

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Methods
  5. Results
  6. Conflicts of interest
  7. References
  8. Appendices

Appendices

  1. Top of page
  2. Abstract
  3. Background and objectives
  4. Methods
  5. Results
  6. Conflicts of interest
  7. References
  8. Appendices

Appendix 1

TreatmentsAuthorsMethodsMain resultsPrimary outcomesSecondary outcomesResults on secondary outcomesEFNS Class
Diabetic Neuropathy
Antidepressants
Duloxetine 60 mg QD or BID vs. placeboRaskin et al. 2005Parallel groups 12 weeks, n = 348Duloxetine QD or BID > placeboNRS pain intensity (average) (diary) baseline to endpointWorst pain, night pain, PGIC, CGIC, BPI, SF-MPQ sensory, dynamic allodynia (examination)All outcome measures similarly improved except allodynia (weak at baseline) but modest difference/placebo (0.87–0.9/ 10 on average pain intensity)I
Duloxetine 20, 60,  120 mg vs. placeboGoldstein et al. 2005Parallel groups, 12 weeks, n = 457Duloxetine > placebo for 60 and 120 mgNRS pain intensity (average) (diary) baseline to endpointAnalgesic use, worst pain, night pain, PGIC, CGIC, BPI, SF-MPQ sensory, dynamic allodyniaAll outcome measures similarly improved except allodynia (weak at baseline)I
Duloxetine 60 BID or QD mg vs. placeboWernicke et al. 2006Parallel groups 12 weeks, n = 334Duloxetine > placeboNRS pain intensity (average) (diary) baseline to endpointAnalgesic use, worst pain, night pain, PGIC, CGIC, BPI, SF-MPQ sensory, dynamic allodyniaAll outcome measures similarly improved except allodynia (weak at baseline)I
Meta-analyses of 3 duloxetine trialsKajdascz et al. 2007 N = 1139 patients (800 duloxetine, 339 placebo) 12 weeksNNT 5.2 (3.8–8.3) for 60 mg/day NNT 4.9 (3.6–7.6) for 120 mg/dayNNT 50% pain relief LOCF and BOCF; NNH based on discontinuation  SR class I
Venlafaxine ER 75–150 mg (flexible) vs. vitamin combination (B1B6)Kadiroglu et al. 2008Parallel groups, 8 weeks, n = 60Venlafaxine > placeboVAS pain intensity at visits (SFMPQ); NRS pain intensity; SFMPQ Categorical responseNo specification of primary and secondary outcomesSignificant effects on all outcome measuresII
Escitalopram 20 mg vs. placeboOtto et al. 2008Cross over, 5 weeks per treatment n = 48 (37 completers)Escitalopram > placebo6 point categorical Pain reliefNRS of total and NP symptoms; paracetamol use: QST, SF36, MDI, NNT, sleepSymptoms equally improved but not analgesic uses and sleep, SF36 and MDII
Antiepileptics
Meta-analysis of gabapentin trials in NP including dia betic NP (Cochrane)Wiffen et al. 20094 placebo controlled studies and 3 active controlled studiesGabapentin > placebo NNT 2.9 (CI 2.2–4.3)NNT 50% pain relief Relative risk  SR class I
Treatments (diabetic neuropathy)AuthorsMethodMain resultsPrimary outcomeSecondary outcomeResults on secondary outcomesEFNS Class
Oxcarbazepine (OXC) 1200 mg vs. placeboGrosskopf et al. 2006Parallel groups 12 weeks, n = 141OXC = placeboVAS pain intensity (average) (electronic diary)Global assessment of therapeutic effects, sleep, SF36, POMSOnly one measure of pain No effect on any measureI
Oxcarbazepine 300–1800 mg vs. placeboDogra et al. 2005Parallel groups 12 weeks, n = 146OXC > placeboVAS pain intensity (average) (electronic diary) NNTGlobal assessment of therapeutic effects (GATE), sleep, SF36, POMSVAS, GATE similar effects; sleep improved but not SF36I
Pregabalin, 150, 600 mg vs. placeboRichter et al. 2005Parallel groups 6 weeks, n = 246Pregabalin > placeboNRS pain intensity (average) (diary) NNT (50% pain relief)Sleep, SF-MPQ (sensory, affective total), VAS pain intensity, PPI(MPQ),SF36, POMS, CGIAll measures improved except SF36 less sensitive (1 domain improved only)I
Pregabalin 600 mg/day vs. placeboArezzo et al. 2008Parallel groups, 13 weeks, n = 167Pregabalin > placeboNRS pain intensity (average) (diary) at endpoint + weekly pain scores, respondersSleep interference (NRS), SFMPQ, VAS and PPI (SFMQP) PGIC, CGIC, + safety parameters (Nerve conduction)Significant effects on all outcome measures No effect on nerve conductionI
Pregabalin 150, 300, 600 mg/day vs. placeboTölle et al. 2008Parallel groups 12 weeks, n = 396Pregabalin > placebo (highest dosage)NRS pain intensity (average) (diary) (endpoint, weekly, 8 weeks)Sleep interference (NRS), PGIC, CGIC, EQ-5D, NNTEffects on all outcomes of the highest dosage only except EQ-5D more sensitive to all dosages; centre effectI
Pregabalin flexible 150–600 mg vs. fixed 600 mg vs. placebo (including PHN patients)Freynhagen et al. 2005Parallel groups 12 weeks, n = 338Pregabalin (fixed, flexible)  > placeboNRS pain intensity (average) (diary) NNT: 30%, 50%MOS-sleep, PGICAll measures equally sensitiveI
Meta-analysis of 7 pregabalin trials in diabetic PNFreeman et al. 2008 N = 1510 (ITT population, 7 studies)Reduction in endpoint least squares mean pain scoresPregabalin > placebo all doses -correlation with doses; 150 mg not effective in single trials but effective in pooled analysisPGIC, safety measures, time to onset of pain relief, NNT 30–50% pain relief, proportion of responders, sleepDiscontinuation rates: absent (150 mg) to 20% (600 mg); other outcome measures improved; Side effects dose-dependentSR class I
Lamotrigine, 200, 300, 400 mg (2 RCTs) vs. placeboVinik et al. 2007Parallel groups, 19 weeks, n = 360 per studyLamotrigine = placebo (LOCF)  > placebo (observed scores)NRS pain intensity (average) (diary) Responders (30%, 50%); Large placebo effectSleep, pain intensity (walking) SF-MPQ, Neuropathic pain scale (NPS), CGI, Rescue analgesicsEnd of trt (observed scores): PGIC, walking pain intensity, NPS:significant for some doses; No effect on other outcomesI
Lamotrigine up to 200 mg vs. amitriptyline up to 75 mgJose et al. 2007Cross over, 6 weeks per trt, n = 53Lamotrigine =  amitriptylinePain relief, overall improvementMcGill pain questionnaire, Likert pain scaleNo difference in secondary outcome but lamotrigine had less side effects (43% vs. 75%)II
Lacosamide 400 mg vs. placeboRauck et al. 2007Parallel groups, 10 weeks, n = 119 (94 completers)Lacosamide > placeboNRS pain intensity (average) (diary) Effect sizeSF-MPQ including VAS-PPI, NPS, sleep (NRS), SF36, POMS, pain free days, CGIMeasures of pain equally improved; No effect on POMS; SF36 only 2 domains improved including painI
Lacosamide 200, 400 and 600 mg vs. placeboWymer et al. 2009Parallel groups 18 weeks, n = 370 (64% completers)Lacosamide 400 mg > placebo; 600 mg > placebo observed casesNRS pain intensity last 4 weeks (diary)Sleep NRS), PGIC, activity (diary)40% discontinuation in the 600 mg group for adverse effects; 23% in the 400 mg (9% placebo)I
Lacosamide 200, 400 and 600 mg vs. placeboShaibani et al. 2009Parallel groups, 12 weeks, n = 468Lacosamide 400 mg approached significance; 600 mg nsNRS pain intensity last 4 weeks (diary)PGIC, responders (50% and 30% pain relief), pain free daysResponders ns improvement; no significant effect on sleepI
Zonisamide 540 mg vs. placeboAtli and Dogra 2005Parallel groups, 12 weeks, n = 25Zonisamide = placeboVAS/NRS pain intensity (average) (diary)- respondersSleep, daily functioning, pain interferenceNo effect on any outcome measuresII
Opioids and tramadol
CR Oxycodone, mean 37 mg (10–99) vs. placeboGimbel et al. 2003 Jensen et al. 2006 (post hoc analysis of NPS)Parallel groups, 6 weeks, n = 159Oxycodone > placeboNRS pain intensity (average) (diary)NRS current/worst pain (diary), satisfaction, sleep scale, BPI interference, Rand Mental Health Inventory, SIP, SF 36, NPS, discontinuation, time to mild pain, days of mild painEffective on all measures of pain but only 2 items of BPI interference and no effect on SF36, Rand, SIP except ambulation NPS:effects on deep, sharp, dull not sensitiveI
CR Oxycodone (Oxy) 10–80 mg +  gabapentin (gaba) (100–3600 mg) vs. placebo+gabapentinHanna et al. 2008Parallel groups, 12 weeks, n = 338Oxy-gaba >  gabapentin-placeboNRS pain intensity (box scale) at each visitRescue analgesics, sleep (n of disturbed night sleeps, quality of sleep), SF- BPI, SF-MPQ, EuroQolAll measures of pain equally improved; Sleep disturbance improved but not quality of sleep-No statistics for EuroQolI
Tramadol 37.5 acetaminophen 325 vs. placebo (up to 1–2 tablets 4 times daily)Freeman et al. 2009Parallel groups, 8 weeks, n = 311Tramadol/APAP >  placeboNRS pain intensity (average) (diary) from baseline to final weekSleep interference, PGIC, QoL, moodAll outcome measures significantly improved Nausea:the only adverse effect; similar discontinuation rates (8.1% for active; 6.5% for placebo)I
Other treatments
SC Botulinum toxin-A (max 300 U) vs. salineYuan et al. 2009Cross over, 12 weeks, n = 20 (18 completers)BTX-A > placeboVAS pain intensity, Pittsburgh sleep quality index, SF36 No primary outcome specified; effects on VAS and sleep (4 weeks) but not SF36II
Glyceryl trinitrate spray (feet) vs. placeboAgrawal et al. 2007Cross over, 4 weeks per trt, n = 48 (43 completers)GTN spray > placeboVAS pain intensity at visitsSFMPQ (total score) NRS pain intensity, PPI, NNT for pain reliefAll outcome measures equally sensitiveII
NK-1 receptor antagonist TKA731 vs. placeboSindrup et al. 2006Parallel groups 2 weeks, n = 87TKA = placeboVAS pain intensity (average) (diary)CGI, rescue medication, sleep questionnaire, VAS for neuropathic symptomsNo effect on any outcome measureI
ABT-594 (150, 225, 300 mg BID) vs. placeboRowbotham et al. 2009Parallel groups, 7 weeks (1 week titration)ABT > placebo for all dosages without dose responseNRS pain intensity final week (diary)NRS pain intensity each week, Proportion of responders, NPS score and symptoms, SF36, rescue medicationResponders improved but too many side effects and dropouts (up to 66%) NPS ns; SF36 only physical subscore improved but mental component deterioratedI
Combination (in diabetic PN and PHN)
Gabapentin, 2207 mg vs. morphine 45 mg vs. combination (morphine 34 mg + gaba 1705 mg) vs. placeboGilron et al. 2005Cross over 5 weeks per trt, n = 57 (41 completers)Gabapentin = placebo Morphine > placebo Combination > mor > gaba And > pboNRS pain intensity (average) (diary)SF-MPQ (sensory affective total, VAS-PPI), BDI, BPI (interference), SF36, MMSE, global pain relief, blindingSFMPQ, BPI, SF36, BDI significant for gabapentin, morphine and combination; NRS less sensitive to gabapentinI
Gabapentin 2433 mg vs. nortriptyline 61.6 mg vs. combination 2180 + 50.1Gilron et al. 2009Cross over, 6 weeks per trt, n = 56 (45 completers)Combination > gabapentin or nor Gabapentin > placeboNor > placeboNRS pain intensity (average) (diary)BPI, SF-MPQ, blinding, SF36Better effects of the combination on BPI, BPI interference with sleep, mood (/nor), SFMPQ, SF36; dry mouth > with nor and weight gain > for gabapentinI
TreatmentsAuthorsMethodMain resultsPrimary outcomeSecondary outcomeResults on secondary outcomesEFNS Class
Post-Herpetic Neuralgia (PHN)
Antidepressants
Fluoxetine 60 mg vs. imipramine 150 mg vs. amitriptyline 150 mgRowbotham et al. 2005Parallel groups, 6 weeks, n = 38Similar effects of the 3 drugsVAS pain intensity (average) at visitsPain relief scale (6 items) BDI, QST (allodynia to brush)VAS and pain relief scale similarly improved Allodynia sensitive to TCAsI
Nortriptyline 25–100 mg vs. gabapentin 300–1200 mg vs. placeboChandra et al. 2006Parallel groups, 8 weeks, n = 76 (70 as intent to treat)Nortriptyline = GabapentinNRS pain intensity (diary) from baseline to end of studyVAS sleep, VAS pain SF-MPQ, disability (categorical scale) pain categorical (0–5) CGI (0–4); proportion responders (50%)No difference in outcome measure between active treatments Categorical scales not commonly used (some not validated)II
Antiepileptics
Meta-analysis of gabapentin in NP including PHN (Cochrane)Wiffen et al. 20092 RCTs of gabapentin vs. placeboGabapentin > placebo NNT 3.9 (95% CI 3–5.7)NNT Relative risk  SR class I
Gabapentin ER 1800 mg/day twice daily or once daily vs. placeboIrving et al. 2009 Jensen et al. 2009 (posthoc analysis of NPS)Parallel groups, n = 158, 4 weeks Enrichment designGabapentin ER > placebo for twice daily administration onlyNRS pain intensity (diary) from baseline to endpointSleep interference score NPSEffects on sleep for twice daily and once daily administration; dizziness and somnolence most common AE Differential effects of gabapentin on NP symptoms (hot, cold, deep)I
Pregabalin 150, 300, 600 mg vs. placeboVan Seventer et al. 2006Parallel groups, 13 weeks n = 370Pregabalin > placeboNRS pain intensity (average) (diary) NNT 30–50% reliefSleep CGI (patient)All measures equally sensitiveI
Pregabalin 150–600 vs. 300 mg vs. placeboStacey et al. 2008Parallel groups 4 weeks, n = 269Pregabalin > placeboNRS pain intensity (diary) (criteria:time to onset of pain relief)% responders (≥30% or 50%); PGIC; VAS (SFMPQ, anxiety); VAS allodynia to brush Daily interference scoresPain/allodynia correlated; more severe baseline allodynia:less response to PGB; odds ratio for ≥50% PR: 1.30 (0.71–2.36)I
Treatments (PHS)AuthorsMethodMain resultsPrimary outcomeSecondary outcomeResults on secondary outcomesEFNS Class
Meta-analysis of pregabalin studies in PHN (Cochrane)Moore et al. 20095 RCTs, n = 1417NNT 50% PR:6.9 (4.8–13) for 150 mg; 5.5 (3.8–8.1) for 300 mg and 4.0 (3.1–5.5) for 600 mgNNT 50% PR, NNH  SR class I
Valproate 1000 mg vs. placeboKochar et al. 2005Parallel groups 8 weeks, = 45Valproate > placeboSF-MPQ, VAS (PPI), NRS, NNTCGI (patient)All measures equally sensitiveII (only results from completers)
Opioids vs. antidepressants
Morphine 91 mg or methadone 15 mg vs. nortriptyline 89 mg or desipramine 63 mg vs. placeboRaja et al. 2002 Edwards et al. 2006 (predictors for response)Cross over, 8 weeks per trt, n = 76 (44 completers of 3 periods)Opioids = tricyclics > placeboNRS pain intensity Pain relief (0%–100%) Cognitive functionPreference with treatment; MPI (physical, sleep) Beck; Treatment preference, NNT (50% PR), QSTAll pain measures improved; effects on sleep and preference with trts; Predictors for response:higher heat pain thresholds at baseline, higher baseline pain, younger ageI
Topical agents
Lidocaine patch, 5% (max 3/day) vs. placebo in PHN patientsBinder et al. 2009Parallel groups, enriched enrolment, 2 weeks per trt after 8 weeks open label run-in phase, n = 265 (71 randomized)No difference in the full analysis set in the primary outcome but only in perprotocol population (n = 34)Time to exitAllodynia to brush, pain relief, SF-MPQ, mean pain intensitySignificant in the perprotocol population; no direct statisti cal comparisons of secondary endpoints between lidocaine and placebo;only 2.8% adverse events in the double blind phase (13.8% for lidocaine in the study including run in period)II (groups not balanced, many early withdrawals)
High concentration capsaicin patch NGX-4010 (8%) vs. low concentrations (0.04%) 60 min in PHNBackonja et al. 2008Parallel groups, Assessment up to 12 weeks N = 402NGX-4010 > placeboNRS average pain intensity (diary) from week 2–8Proportion of responders (30% pain relief); Gracely pain scale, SFMPQ, PGIC, CGIC; BPI; SF36, Self assessment of treatment (SAT); concomitant treatmentsEffects on pain, PGIC, SAT but no significant effects on BPI, SFMPQ, SF36, ≥50% reduction pain (not shown); no effect on rescue medication – blinding perhaps compromised due to more initial pain in the high concentration patchI
Others
COX-2 inhibitor (GW40381) 25 or 50 mg vs. placeboShackelford et al. 2009Parallel groups, 3 weeks N = 209COX-2 = placebo but duration of trial may be too shortNRS average pain intensity (diary) from baseline to last weekNPS; allodynie severity (brush) SF-MPQ; PGIC; CGIC; PR score; discon tinuation due to lack of effect:rescue medicationNo statistical effect on primary and secondary endpoints except for the NPS in the 25 mg groupII
Meta-analysis of drug treatmentsHempestall et al. 200525 analysable RCTsNNT for TCA combined 2.64 (2.43–7.99); NNT for gabapentin 4.39 (3.34–6.07) NNT for opioids 2.67 (2.07–3.77); NNT for tramadol 4.76 (2.61–26.97)NNT, NNH, ratio NNT/NNH  SR class I
TreatmentsAuthorsMethodMain resultsPrimary outcomeSecondary outcomeResults on secondary outcomesEFNS Class
  1. BDI, Beck depression inventory; BOCF, baseline observation carried forward; BPI, Brief pain inventory; CGIC, clinical global impression of change; HDRS, Hamilton depression rating scale; LANSS, Leeds assessment of neuropathic symptoms and signs; LOCF, last observation carried forward; MDI, major depression inventory; MMSE, mini mental scale examination; MPI, Multidimensional Pain inventory; MPQ, Mc Gill Pain questionnaire; NIS, Neuropathy impairment score; NNT, number needed to treat; NPS, neuropathic pain scale; NPSI, neuropathic pain symptom inventory; NRS, numerical rating scale (or Likert scale); NS, not significant; NWC, number of words chosen; PDI, Pain disability index; PHN, post herpetic neuralgia; PN, polyneuropathy; PGIC, patient clinical global impression; POMS, profile of mood scale; PPI, present pain intensity; PR, pain relief; QOL, quality of life; QST, quantitative sensory testing; RCT, randomized controlled trial; SF-MPQ, short form Mc Gill pain questionnaire; SIP, Sickness Impact Profile; SF36, Short Form 36 (QoL measure); STAI, Spielberger trait anxiety inventory; Trt, treatment; VAS, visual analogue scale; VRS, Verbal rating scale; vs., versus.

Trigeminal Neuralgia
Systematic review and guidelines of diagnosis and treatment including drug treatments in trigeminal neuralgiaCruccu et al. 2009 Gronseth et al. 2008SR of all treatments in TN including drugs; 12 RCTs analysedCBZ: NNT = 1.8 (1.3–2.2) one class II and 1 class II trial (n = 147); OXC 600–1800 mg similar effect as CBZ on number of attacks and global assessment in 2 class II RCTs (n = 130); other drugs have poor efficacy or effective in single trialsEfficacy on number of attacks, paroxysmal pain, brush-evoked pain, and global assessmentAdverse events SR class I
Central Pain
Amitriptyline 150 mg vs. gabapentin 3600 mg vs. placebo (diphenhydramine) SCI painRintala et al. 2007Cross over 8 week per trt n = 38 (22 completers)Amitriptyline > gabapentin Gabapentin = placeboVAS pain intensity (average) at visitsProportion responders (30%) VAS pain intensity (worst) Rescue analgesicsVAS and proportion responders responsive to trts No effect on rescue trtsII
Tramadol 150 mg vs. placebo SCI painNorrbrink and Lunderberg 2009Cross over,  4 weeks, = 36 (35 analysable)Tramadol > placeboNRS pain intensityMultidimensional Pain Inventory; HAD; sleep questionnaire; PGIC; Brush induced allodynia (tooth-brush); pain unpleasantness, maximal and minimal pain (NRS)Diff./placebo on pain intensity, PGIC, anxiety, sleep but not mood, pain unpleasantness, pain interference, distress. 43% of withdrawal due to side effects with tramadol vs. 17% placeboII
Pregabalin, 150–600 mg vs. placebo (SCI pain)Siddal et al. 2006Parallel groups, 8 weeks n = 137Pregabalin > placeboNRS pain intensity (average) (diary)SF-MPQ, % responders (30, 50%), sleep, POMS, CGIAll measures of pain equally sensitive 21% discontinuation for adverse events vs. 13% placeboI
Pregabalin, 150–600 mg vs. placebo (SCI, brain)Vranken et al. 2008Parallel groups 4 weeks n = 40Pregabalin > placeboVAS pain intensity (average) at weekly visitsSF36, EuroQol, PDIOnly one measure of pain; PDI and SF36 less sensitive than EQD5 (SF36 -pain improved)I
Lamotrigine up to 400 mg vs. placebo (multiple sclerosis)Breuer et al. 2007Cross over, 11 weeks per trt n = 12Lamotrigine = placebo Inclusion criteria 4/10 on any NPS itemNRS pain intensity from the BPI (worst, least, average pain) (diary) Responders from BPI average pain (>30%)Rescue analgesics, NPS Multiple sclerosis QOL-54 BPI-interferencePain responses similar but NS; Carryover effect for the item «sensitive» of the NPS; underpowered studyII
Levetiracetam 500–3000 mg/day vs. placebo (SCI pain)Finnerup et al. 2009Cross over, 5 weeks per tret, washout 1 week n = 36 (24 completers)Levetiracetam = placeboAverage pain intensity (NRS)Pain relief (categorical), MPQ, NPSI, proportion of pain relief (33%), sleep interference, use of rescue analgesics, evoked pain (pinprick, brush, cold evoked), PGIC, spasm (NRS, Penn), Ashworth, blindnessNo effect on any outcome measure Possibly underpowered for secondary outcome measures (evoked pain, spasms)II
S-ketamine iontophoretic transdermal 50 and 75 mg vs. placebo (NP screened with LANSS)Vranken et al. 2005Parallel groups 7 days n = 33Ketamine = placebo (primary outcome)VAS pain intensity at each visitMeasures of quality of life and disability:PDI, EuroQol, SF 3No effect on pain but effects on all measures of QOL with the high dosageI
THC/cannabidiol (CBD) 2.7/2.5 oromucosal vs. placebo max 48 sprays/dayRog et al. 2005Parallel groups 5 weeks n = 64THC/CBD > placeboNRS pain intensity (average) (diary)Sleep NRS NPS cognitive function HADS-Multiple sclerosis related disability CGI (patient)Pb with NP screening (some had spasticity) Similar effects on NRS, total score NPS and sleep NPS:signifi cant effect for some items (intense, dull, sensitive)I
Tramadol 1–1.5 mg/kg per 6 hArbaiza et al. 2007Parallel groups 6 weeks n = 36Tramadol > placeboNRS pain intensity at each visitKarnovsky scale, ADL including sleep and appetite (yes/no), Zung depression, Beck anxiety, SEPs, AED use on a scale (0–5)Non validated scales (AED use, ADL) Similar effects on pain, AED rescue, Karnovski, ADL, but not moodII
Other Neuropathic Pain Conditions
HIV neuropathy
Memantine 40 mg/day or max tolerated dose vs. placeboSchiffito et al. 2006Parallel groups 16 weeks n = 45Memantine = placeboVAS pain and paresthesia intensity at 16 weeks No effects on pain or paresthesiaII
Smoked cannabis (3.56% THC) vs. placebo cigarettes; 1 cig TIDAbrams et al. 2007Parallel groups 5 days n = 55Smoked cannabis > placeboVAS pain intensity (average) (diary)Current pain VAS (immediate effect) NNT 30% pain relief Pain intensity (VAS) induced by 45°C for 1 mn; Heat/capsaicin sensitization; POMSMeasures of pain improved No effect on pain induced by heat but attenuation of heat/capsaicin hyperalgesia at day 1 No effect on the POMSI
Smoked cannabis (1 and 8% THC) vs. placeboEllis et al. 2009Cross over 5 days n = 34Smoked cannabis > placeboPain intensity (Descriptor Differential Scale)Mood and functioning Proportion of responders (30% pain relief)Significant effects on pain but no difference on mood and functioningII
High concentration capsaicin patch NGX-4010 (8%) vs. low concentrations (during 30, 60, 90 mn) in HIV neuropathySimpson et al. 2008Parallel groups, Assessment up to 12 weeks n = 307 (274 completers)NGX-4010 > placeboNRS average pain intensity (diary) from week 2–12% change in NRS present, worst pain intensity (diary) % change from baseline of average NRS; proportion responder (30% pain relief); Gracely pain scale, SFMPQ, PGIC, CGIC; BPI composite score; QSTAll measures equally sensitive to treatment No effect on sensory functionI
Nerve trauma
Gabapentin up to 2400 mg vs. placeboGordh et al. 2008Cross over 5 weeks per trt, n = 120 VAS ≥ 3 at inclusionGabapentin = placebo on the primary outcome Placebo effect superior during the first periodVAS pain intensity (present pain twice a day) (electronic diary % responders (30%, 50% pain relief)Pain relief (categorical), sleep interference (VAS electronic diary), SF36, CGI, rescue analgesicsPR and PGIC more improved than VAS; sleep significant; 3 items of the SF36 improved; NNT depends on the measureI
Treatments (other conditions)AuthorsMethodsMain resultsPrimary outcomeSecondary outcomeResults on secondary outcomesEFNS Class
Levetiracetam 3000 mg/day vs. placeboVilholm et al. 2008Parallel groups, 4 weeks n = 27 (25 completers)Levetiracetam = PlaceboNRS pain intensity, relief, NP symptoms; rescue analgesics; QSTNo specification of primary and secondary endpointsNo effect on any outcomeII
SC Botulinum toxin A (BTX-A) (max 200 U) vs. saline in peripheral neuropathic pain (traumatic, PHN) with allodyniaRanoux et al. 2008Parallel groups 6 months = 29BTX-A > placeboNRS pain intensity (average) (diary)NNT 50% pain relief PGIC, % pain relief, NPSI, average pain VAS at each visit, QST(area of allodynia to brush and punctate, thermal testing) BPI-interference, HAD Blinding assessmentEffect on global pain/pain relief and CGI similar Better effect on NPSI symptoms/ dimensions (burning, paroxysmal pain, allodynia); Only 2 items of BPI-inter ference improved Predictors of response based on QST (patients with severe thermal deficits less improved)I
Phantom pain
Gabapentin, 300–3600 mg vs. placeboSmith et al., 2005Cross over, 6 weeks, n = 24Gabapentin = placeboNRS Pain intensityCategorical pain relief scale, benefit and side effects; BPI; blinding; SF-MPQ; CES-D; FIM; SWLS; CHARTNo effect on any outcome measures Categorical scales not validatedII
Morphine 112 mg vs. mexiletine 933 mg vs. placeboWu et al. 2008Cross over 6 weeks per trt wash out 1 week n = 60Morphine > placebo and mexiletineNRS pain intensity (averagediary) throughout the study (stump and phantom mixed)% pain relief (0–100%) NNT for 50 and 33% pain relief, functional activity (MPI) (general and ntererence scales)Effects on pain but not on self reported levels of activityI
Cancer NP
Gabapentin 600–1800 mg vs. placebo (cancer NP)Caraceni et al. 2005Parallel groups, 10 days n = 121Gabapentin > placeboNRS pain intensity (average) (diary)Neuropathic symptoms NNT 33% pain relief Allodynia at examination Rescue analgesicsEffects on pain intensity but not on analgesic use or on neuropathic symptomI
Radiculopathies
Nortriptyline 25–100 mg vs. morphine 15–90 mg vs. combination vs. placeboKhoromi et al. 2007Cross over 7 weeks per trt n = 55 (28 completers)No effect of treatmentsNRS pain intensity (average and maximal) (diary)Global pain relief (categorical) Oswestry disability scale BDI, SF-36, NNT (pain relief) BlindingAverage pain: ns -Combination > placebo for worst pain and pain relief/placebo (chance effect?) No blindingII
Topiramate 200 mg vs. diphenhydramine 40 mgKhoromi et al. 2005Cross over 6 weeks per trt n = 41 (29 completers)Topiramate marginally > placebo (primary outcome)NRS pain intensity (average) (diary) for leg painNRS pain intensity (back, global pain), worst pain, Pain relief (categorical) Oswestry, BDI, SF36Average leg pain less improved than global assessment or worst painII
Pregabalin 150–600 mg vs. placeboPfizer, protocol A0081007 –20 may 2008Single blind run in phases with placebo then pregabalin, then 5 weeks double blind period, n = 217 (187 completers)Pregabalin = placeboIncrease in pain over the double blind treatment period in patients randomized to placebo compared to pregabalinPGIC, sleep interference, HADS, EQ-5D, MOS, pain treatment satisfaction scale, Roland Morris disabilityNo effect on any outcome measureII (numerous protocol violations)
Multiaetiology NP
Gabapentin 600–1800 mg vs. placeboYelland et al. 2009N of 1 method, 3 double-blind RCT cross over trials N = 73 (48 completes)Only 29% patients showed a positive response to gabapentin, 69% no differenceAggregate measure for: VAS for pain intensity, sleep-VAS, functional limitation VAS, treatment preference,side effects  II many withdrawals (35%)
Lamotrigine 200, 300, 400 mg. vs. placeboSilver et al. 2007Parallel group, 14 weeks n = 220Lamotrigine = placebo Large placebo effectNRS pain intensity (average) (diary), responders (30%, 50%)Sleep interference SF-MPQ, NPS total score Rescue analgesics, CGINo difference/placebo, No outcome measure more sensitive -No predictors – dizziness, rash, somnolence in >5% of patientsI
Lidocaine patch, 5% (max 4/day) vs. placebo in patients with allodynia (PHN, postsurgical, peripheral neuropathy)Meier et al. 2003 Wasner et al. 2005 (subgroup analysis)Cross over 7 days per trt n = 40Lidocaine > placeboVAS spontaneous pain and allodynia intensity (diary)Descriptors partially derived from the MPQ QOL (how did you sleep) on a 5-point categ scale; NNT for 50% pain relief and allodynia relief; effect size QST and QSART in a subgroup of 18 PHN patientsShort period assessment (7 days)- Non validated scales (symptoms, sleep); Better effect on ongoing pain/allodynia (NNT) - ES 0.4; Reduction in number of symptoms only; sleep ns, Better effects of lidocaine in patients with impairment of nociceptor functionI (II for Wasner et al.)
Lidocaine patch 5% vs. topical amitriptyline (ami) 5% vs. placeboHo et al. 2008Cross over 1 week per trt, n = 35Amitriptyline = lidocaine = placebo; Lido-caine>amiVAS pain intensity at the end of trt periodDaily NRS, MPQ, rescue analgesics, patient satisfaction(categorical), degree of pain reliefOutcome measures equally improvedII
Topical amitriptyline 2% vs. topical keta mine 1% vs. combi nation vs. placeboLynch et al. 2005Parallel groups 3 weeks n = 92Ami = ketamine = combination = placeboNRS pain intensity (average) (diary)SF-MPQ, dynamic allodynia, pinprick hyperalgesia, PDI, patient satisfactionNo effect on any outcome measureI
Venlafaxine 75 mg vs. 150 mg vs. placeboYucel et al. 2004Parallel groups 8 weeks n = 55Venlafaxine = placeboVAS pain intensity (VAS-PI) (average) at visitsPatient satisfaction (categorical) Effect on daily activities Rescue analgesics Global efficacy QST (allodynia)VAS-PI reduced in the 3 groups (placebo effect); No effect on rescue analgesics- Slight effect on satisfaction and daily activity (75 mg); Effects on brush-induced allodynia (QST) > PIII
Nabilone 2 mg vs. dihydrocodeine 240 mgFrank et al. 2009Cross over, 6 weeks (2 weeks washout) n = 96 (73 available)Nabilone <  DihydrocodeineVAS pain intensityAnxiety and depression (HAD), SF36, sleep (numbers of hours slept each night)Dihydrocodeine > nabilone on all outcomes but effect moderate in all cases Effect of nabilone on the role physical of SF36I
THC/CBD oromucosal 2.7/2.5 vs. placebo-max 8 sprays/2 h self-titration (peripheral NP)Nurmikko et al. 2007Parallel groups, 5 weeks, n = 125Sativex > placeboNRS pain intensity (average) (diary)NPS, PDI, PGIC pain and allodynia, GHQ-12 (mood, anxiety); NRS sleep; Cognitive tests; allodynia (dynamic, punctate); NNT ongoing pain, allodyniaAll measures of pain improved – no change in pain threshold but decrease in pain evoked by punctate stimuli No effect on CHG-QI

Appendix 2

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Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindstrom T, Thorell LH. A comparison a amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain 1997; 13: 313–323 (class I).

Wernicke JF, Pritchett YL, D’Souza DN, Waninger A, Tran P, Lyengar S, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006; 67: 1411–1420 (class I).

Wymer JP, Simpson J, Sen J, Bongardt S. Efficacy and safety of lacosamide in diabetic neuropathic pain: a 18 weeks double blind placebo controlled trial of fixed doses regimens. Clin J Pain 2009; 25: 376–385 (class I).

Yuan RY, Sheu JJ, Yu JM, Chen WT, Tseng IJ, Chang HH, et al. Botulinum toxin for diabetic neuropathic pain: a randomized double-blind crossover trial. Neurology 2009; 72: 1473–1478 (class II).

Yuen KC, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled cross-over study. Diabetes Care 2002; 25: 1699–1703 (class I).

Systematic reviews and RCTs in postherpetic neuralgia

Arezzo JC, Rosenstock J, La Moreaux L, Pauer L. Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial. BMC Nerurology 2008; 8: 33.

Armstrong DG, Chappell AS, Le TK, Kajdasz DK, Backonja M, D’Souza DN, et al. Duloxetine for the management of diabetic peripheral neuropathic pain: evaluation of functional outcomes. Pain Med 2007; 8: 410–418 (SR class I).

Atli A, Dogra S. Zonisamide in the treatment of painful diabetic neuropathy: a randomized, double-blind, placebo-controlled pilot study. Pain Med 2005; 6: 225–234 (class II).

Bernstein JE, Korman NJ, Bickers DR, Dahl MV, Millikan LE. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989; 21: 265–270 (class II).

Binder A, Bruxelle J, Rogers P, Hans G, Böster I, Baron R. Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia. Clin Drug Investig 2009; 29: 393–408 (class I).

Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo- controlled trial. Pain 2003; 104: 323–331 (class I).

Chandra K, Shafiq N, Pandhi P, Gupta S, Malhotra S. Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial – the GONIP Trial. Int J Clin Pharmacol Ther 2006; 44: 358–363 (class II).

Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003; 60: 1274–1283 (class I).

Dubinsky RM, Kabbani H, El-Chami Z, Boutwell C, Ali H. Practice parameter: treatment of postherpetic neuralgia. An evidence-based report of the Quality Standards Committee of the American Academy of Neurology. Neurology 2004; 63: 959–965 (class I SR).

Edwards RR, Haythornthwaite JA, Tella P, Max MB, Raja S. Basal heat pain thresholds predict opioid analgesia in patients with postherpetic neuralgia. Anesthesiology 2006; 104: 1243–1248 (class II).

Eisenberg E, Kleiser A, Dortort A, Haim T, Yarnitsky D. The NMDA (N-methyl-D-aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: a double-blind, placebo-controlled study. Eur J Pain 1998; 2: 321–327 (class II).

Galer BS, Jensen MP, Ma T, Davies PS, Rowbotham MC. The lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale. Clin J Pain 2002; 18: 297–301 (class II).

Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enrichment enrollment study. Pain 1999; 80: 533–538 (class II).

Graff-Radford SB, Shaw LR, Naliboff BN. Amitriptyline and fluphenazine in the treatment of postherpetic neuralgia. Clin J Pain 2000; 16: 188–192 (class III).

Hans G, Sabatowski R, Binder A, Boesl I, Rogers P, Baron R. Efficacy and tolerability of a 5% lidocaine medicated plaster for the topical treatment of post-herpetic neuralgia: results of a long-term study. Curr Med Res Opin 2009; 25: 1295–305 (class IV).

Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2005; 2: e164 (class I SR).

Irving G, Jensen M, Cramer M, Wu J, Chiang Y-K, Tark M. Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia. Clin J Pain 2009; 25: 185–192 (class I).

Jensen MP, Chiang Y-K, Wu, J. Assessment of pain quality in a clinical trial of gabapentin extended release for postherpetic neuralgia. Clin J Pain 2009; 25: 286–292 (class II).

Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev 2007; 18: CD004846 (class I SR).

Kishore-Kumar R, Max MB, Schafer SC, Gaughan AM, Smoller B, Gracely RH, et al. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther 1990; 47: 305–312 (class II).

Kochar DK, Garg P, Bumb, Kochar SK, Mehta RD, Beniwal R, et al. Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study. Q J Med 2005; 98: 29–34 (class II).

Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 1988; 38: 1427–1432 (class II).

Raja SN, Haythornwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, et al. Opioids versus antidepressants in postherpetic neuralgia. Neurology 2002; 59: 1015–1021 (class I).

Rice ACR, Maton S, Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double-blind, placebo-controlled study. Pain 2001; 94: 215–224 (class I).

Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280: 1837–1842 (class I).

Rowbotham MC, Reisner LA, Davies PS, Fields HL. Treatment response in antidepressant-naive postherpetic neuralgia patients: double-blind, randomized trial. J Pain 2005; 6: 741–746 (class I).

Sabatowski R, Galvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004; 109: 26–35 (class I).

Shackelford S, Rauck R, Quessy S, Blum D, Hodge R, Philipson R. A randomized, double-blind, placebo controlled trial of a selective COX2 inhibitor GW406381 in patients with postherpetic neuralgia. J Pain 2009; 10: 654–660 (class I).

Stacey BR, Barrett JA, Whalen E, Phillips KF, Rowbotham MC. Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain 2008; 9: 1006–1017 (class I).

Van Seventer R, Feister HA, Young JP Jr, Stoker M, Versavel M, Rigaudy L. Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin 2006; 22: 375–384 (class I).

Wasner G, Kleinert A, Binder A, Schattschneider J, Baron R. Postherpetic neuralgia: topical lidocaine is effective in nociceptor deprived skin. J Neurol 2005; 677–676 (class II).

Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998b; 50: 1837–184 (class I).

Watson CP, Chipman M, Reed K, Evans RJ, Birkett N. Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. Pain 1992; 48: 29–36 (class II).

Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitryptiline versus placebo in post-herpetic neuralgia. Neurology 1982; 32: 671–673 (class II).

Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003; 105: 71–78 (class I).

Watson CP, Tyler KL, Bickers DR, Millikan LE, Smith S, Coleman E. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993; 15: 510–526 (class I).

Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 1998a; 51: 1166–1171 (class II).

Systematic reviews and RCTs in trigeminal neuralgia

Campbell FG, Graham JG, and Zilkha KJ. Clinical trial of carbamazepine (tegretol) in trigeminal neuralgia. J Neurol Neurosurg Psychiatry 1966; 29: 265–267.

Carrazana E, Mikoshiba E. Rationale and evidence for the use of oxcarbazepine in neuropathic pain. J Pain Symptom Manag 2003; 25: S31–S35.

Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol 2008; 15: 1013–1028 (class I SR).

Cruccu G, Truini A Trigeminal neuralgia and orofacial pains. In: The Neurological Basis of Pain. New York: McGraw Hill, 2005: 401–414, (class I SR).

Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology 2008; 71: 1183–1190 (class I SR).

He L, Wu B, Zhou M. Non-antiepileptic drugs for trigeminal neuralgia. Cochrane Database Syst Rev 2006; 3: CD004029 (class I SR).

Lemos L, Flores S, Oliveira P, Almeida A. Gabapentin supplemented with ropivacain block of trigger points improves pain control and quality of life in trigeminal neuralgia patients when compared with gabapentin alone. Clin J Pain 2008; 24: 64–75 (class IV).

Liebel JT, Menger N, Langohr H. Oxcarbazepine in der Behandlung der Trigeminus neuralgie. Nervenheilkunde 2001; 20: 461–465 (class II).

Nurmikko T, Cruccu G. Botulinum toxin for trigeminal neuralgia. Eur J Neurol 2009; 16: e104 (comment).

Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens EL. Lamotrigine (lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain 1997; 73: 223–230 (class III).

Systematic reviews and RCTs in central pain

Breuer B, Pappagallo M, Knotkova H, Guleyupoglu N, Wallenstein S, Portenoy RK. A randomized, double-blind, placebo-controlled, two-period, crossover, pilot trial of lamotrigine in patients with central pain due to multiple sclerosis. Clin Ther 2007; 29: 2022–2030 (class II).

Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD. Efficacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized controlled trial. Pain 2002; 96: 365–373 (class II).

Chiou-Tan FY, Tuel SM, Johnson JC, Priebe MM, Hirsh DD, Strayer JR. Effect of mexiletine on spinal cord injury dysesthetic pain. Am J Phys Med Rehabil 1996; 75: 84–87 (class I).

Djaldetti R, Yust-Katz S, Kolianov V, Melamed E, Dabby R. The effect of duloxetine on primary pain symptoms in Parkinson disease. Clin Neuropharmacol 2007; 30: 201–205 (class IV).

Drewes AM, Andreasen A, Poulsen LH. Valproate for treatment of chronic central pain after spinal cord injury. A double-blind cross-over study. Paraplegia 1994; 32: 565–569 (class II).

Finnerup NB, Sindrup SH, Bach FW, Johannesen IL, Jensen TS. Lamotrigine in spinal cord injury pain: a randomized controlled trial. Pain 2002; 96: 375–383 (class II).

Klit H, Finnerup NB, Jensen TS. Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol 2009; (in press) (class I SR).

Norrbrink C, Lundeberg T Tramadol in neuropathic pain after spinal cord injury: a randomized double blind placebo-controlled trial. Clin J Pain 25: 177–184 (class II).

Leijon G, Boivie J. Central post-stroke pain – a controlled trial of amitriptyline and carbamazepine. Pain 1989; 36: 27–36 (class II).

Levendoglu F, Ogun CO, Ozerbil O, Ogün TC, Ugurlu H. Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury. Spine 2004; 29: 743–751 (class II).

Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehab 2007; 88: 1547–1560 (class II).

Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65: 812–819 (class I).

Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther 2007; 29: 2068–2079 (class IV).

Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology 2006; 67: 1792–1800 (class I).

Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 2004; 329: 253 (class I).

Vestergaard K, Andersen G, Gottrup H, Kristensen BT, Jensen TS. Lamotrigine for central poststroke pain: A randomized controlled trial. Neurology 2001; 56: 184–190 (class I).

Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004; 10: 434–441 (class II).

Vranken JH, Dijkgraaf MG, Kruis MR, Van Dasselaar NT, Van der Vegt MH. Iontophoretic administration of S(+)-ketamine in patients with intractable central pain: a placebo-controlled trial. Pain 2005; 118: 224–231 (class II).

Vranken JH, Dijkgraaf MG, Kruis MR, van der Vegt MH, Hollmann MW, Heesen M. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain 2008; 136: 150–157 (class I).

RCTs in other NP conditions

Arbaiza D, Vidal O. Tramadol in the treatment of neuropathic cancer pain: a double-blind, placebo-controlled study. Clin Drug Investig 2007; 27: 75–83 (class I).

Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain 2004; 112: 299–306 (class II).

Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: a randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med 2002; 27: 481–486 (class II).

Caraceni A, Zecca E, Bonezzi C, Arcuri E, Yaya Tur R, Maltoni M. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004; 22: 2909–2917.

Harke H, Gretenkort P, Ladleif HU, Rahman S, Harke G, Martini C, et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 2004; 22: 2909–2917 (class I).

Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW. The use of oral mexiletine for the treatment of pain after peripheral nerve injury. Anesthesiology 1992; 76: 513–517 (class I).

Ellison N, Loprinzi CL, Kugler J, Hatfield AK, Miser A, Sloan JA, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 1997; 15: 2974–2980 (class I).

Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ 2008; 336: 199–201 (class I).

Gordh TE, Stubhaug A, Jensen TS, Arnèr S, Biber B, Boivie J, et al. Gabapentin in traumatic nerve injury pain: a randomized, double-blind, placebo-controlled, cross-over, multi-center study. Pain 2008; 138: 255–266 (class I).

Hardy JR, Rees EA, Gwilliam B, Ling J, Broadley K, A’Hern R. A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-O The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Analg 2001; 92: 488–495 (class II).

Ho KY, Huh BK, White WD, Yeh CC, Miller EJ. Topical amitriptyline versus lidocaine in the treatment of neuropathic pain. Clin J Pain 2008; 24: 51–55 (class II).

Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization. Pain 90: 47–55. J Clin Oncol 2004; 22: 2909–2017 (class II).

Kalso E, Tasmuth T, Neuvonen PJ. Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. Pain 1996; 64: 293–302 (class II).

Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003; 290: 1757–1762 (class I).

Khoromi S, Cui L, Nackers L, Max MB. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. Pain 2007; 130: 66–75 (class II).

Khoromi S, Patsalides A, Parada S, Salehi V, Meegan JM, Max MB. Topiramate in chronic lumbar radicular pain. J Pain 2005; 6: 829–836 (class II).

Langohr HD, Stohr M, Petruch F. An open and double-blind cross-over study on the efficacy of clomipramine (Anafranil) in patients with painful mono- and polyneuropathies. Eur Neurol 1982; 21: 309–317 (class II).

Lynch ME, Clark AJ, Sawynok J. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain 2003; 19: 323–328 (class II).

Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Anesthesiology 2005; 103: 140 (class I).

Maier C, Dertwinkel R, Mansourian N, Hosbach I, Schwenkreis P, Senne I, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain – results of a randomized double-blinded, placebo-controlled trial. Pain 2003; 103: 277–283 (class II).

McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol 2000; 49: 574–579 (class II).

McCleane GJ. 200 mg daily of lamotrigine has no analgesic effect in neuropathic pain: a randomised, double-blind, placebo controlled trial. Pain 1999; 83: 105–107 (class II).

McCleane GJ. A randomised, double blind, placebo controlled crossover study of the cholecystokinin 2 antagonist L-365,260 as an adjunct to strong opioids in chronic human neuropathic pain. Neurosci Lett 2003; 338: 151–154.

McQuay HJ, Carroll D, Jadad AR, Glynn CJ, Jack T, Moore RA, et al. Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design. Pain 1994; 59: 127–133 (class II).

Meier T, Wasner G, Faust M, Kuntzer T. Ochsner F, Hueppe M. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 2003 (class I).

Mercadante S, Arcuri E, Tirelli W, Villari P, Casuccio A. Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study. Tumori 2002; 88: 239–242 (class II).

Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliat Med 2003; 17: 576–587 (class II).

Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997; 48: 1212–1218 (class I).

Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 2007; 133: 210–220 (class I).

Panerai AE, Monza G, Movilia P, Bianchi M, Francucci BM, Tiengo M. A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain. Acta Neurol Scand 1990; 82: 34–38 (class II).

Ranoux D, Attal N, Morain F, Bouhassira D Botulinum toxin a induces direct analgesic effects in neuropathic pain: a double blind placebo controlled study. Ann Neurol 2008; 64: 274–283 (class I).

Robinson LR, Czerniecki JM, Ehde DM, Edwards WT, Judish DA, Goldberg ML, et al. Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Arch Phys Med Rehabil 2004; 85: 1–6 (class II).

Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. New Eng J Med 2003; 348: 1223–1232 (class I).

Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia. Efficacy and dose-response trials. Anesthesiology 2002; 96: 1053–1061 (class I).

Scadding JW, Wall PD, Parry CB, Brooks DM. Clinical trial of propranolol in post-traumatic neuralgia. Pain 1982; 14: 283–292 (class II).

Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001; 57: 1583–1588 (class I).

Serpell MG. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain 2002; 99: 557–566 (class I).

Silver M, Blum D, Grainger J. Double blind placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain. J Pain Symptom Manage 2007; 34: 446–454 (class I).

Smith DG, Ehde DM, Hanley MA, Campbell KM, Jensen MP, Hoffman AJ, et al. Efficacy of gabapentin in treating chronic phantom limb and residual limb pain. J Rehabil Res Dev 2005; 42: 645–654 (class II).

Tasmuth T, Hartel B, Kalso E. Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain 2002; 6: 17–24 (class II).

Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Effect of levetiracetam on the postmastectomy pain syndrome. Eur J Neurol 2008; 15: 851–857 (class II).

Wallace MS, Magnuson S, Ridgeway B. Efficacy of oral mexiletine for neuropathic pain with allodynia: a double-blind, placebo-controlled, crossover study. Reg Anesth Pain Med 2000; 25: 459–467 (class I).

Wallace MS, Rowbotham M, Bennett GJ, Jensen TS, Pladna R, Quessy S. A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain. J Pain 2002b; 3: 227–233 (class II).

Wallace MS, Rowbotham MC, Katz NP, Dworkin RH, Dotson RM, Galer BS, et al. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 2002a; 59: 1694–1700 (class I).

Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992; 51: 375–379 (class II)

Wilder-Smith CH, Hill LT, Laurent S. Postamputation pain and sensory changes in treatment-naive patients: characteristics and responses to treatment with tramadol, amitriptyline, and placebo. Anesthesiology 2005; 103: 619–628 (class II).

Wu CL, Agarwal S, Tella PK, Klick B, Clark MR, Haythornthwaite JA, et al. Morphine versus mexiletine for treatment of postamputation pain: a randomized, placebo-controlled, crossover trial. Anesthesiology 2008; 109: 289–296 (class I).

Yucel A, Ozyalcin S, Koknel Talu G, Kiziltan E, Yucel B, Andersen OK, et al. The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study. Eur J Pain 2005; 9: 407–416 (class II).