The DOI matches its Crossref record; 80 of the 80 references it cites were found in a registry or an index; 1 of the 45 sources its claims cite were checked for support.
Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis
Open accessAbstract
Background New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.Methods Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.Interpretation Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.Funding NeuPSIG of the International Association for the Study of Pain.
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44 Own result · 24 Not checked yet · 8 Own interpretation · 5 No basis given · 3 Own method · 1 Supported
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“Studies published in peer-review journals reported greater effects than online studies (R2=9·3%, p<0·01).”
- Also stated in: § Risk of bias across studies · plain
“Using meta-regression, we identified that studies published in peer-review journals reported greater treatment effects (OR=2·2, 95% CI 1·5–3·0, n=153; adjusted R2=9·3%, p<0·01) than studies identified via online repositories (OR=1·4, 1·0–1·9, n=17).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
plaincorrelationaln = 153 ·- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Risk of bias across studies · plain
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“6·3 (95 % CI 5·0–8·3) for gabapentin”
- Also stated in: § Quantitative data for individual drugs or drug classes · plain
“Combined NNT was 6·3 (5·0–8·3) for gabapentin and 8·3 (6·2–13) for gabapentin ER/enacarbil.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
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- Also stated in: § Quantitative data for individual drugs or drug classes · plain
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“In total 229 studies were included.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
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“Data for cannabinoids, tapentadol, drug combinations, and several other antiepileptics, antidepressants and topical drugs were inconclusive.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
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“7·7 (95 % CI 6·5–9·4) for pregabalin”
- Also stated in: § Quantitative data for individual drugs or drug classes · plain
“Combined NNT was 7·7 (6·5–9·4) and NNH was 13·9 (11·6–17·4).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
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- Also stated in: § Quantitative data for individual drugs or drug classes · plain
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“NNTs were 3·6 (95 % CI 3·0–4·4) for tricyclic antidepressants (TCAs)”
- Also stated in: § Quantitative data for individual drugs or drug classes · plain
“Combined NNT (15 studies) was 3·6 (3·0–4·4) and NNH was 13·4 (9·3–24·4).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
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- Also stated in: § Quantitative data for individual drugs or drug classes · plain
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“Trial outcomes were generally modest even for effective drugs”
- Also stated in: § Discussion · plain
“Results of quantitative data for individual drugs, showing NNT for 50 % pain relief ranging from around 4 to 10 across most positive trials, emphasizes the overall modest study outcomes in neuropathic pain.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
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- Also stated in: § Discussion · plain
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“6·4 (95 % CI 5·2–8·4) for serotonin- noradrenaline reuptake inbibitor (SNRI) antidepressants duloxetine and venlafaxine”
- Also stated in: § Quantitative data for individual drugs or drug classes · plain
“Combined NNT was 6·4 (5·2–8·4) and NNH was 11·8 (9·5–15·2).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Quantitative data for individual drugs or drug classes · plain
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“Analysis of publication bias suggested a 10% overstatement of treatment effects.”
- Also stated in: § Risk of bias across studies · hedged
“This suggests a 10% relative overstatement of treatment effects.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
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- Also stated in: § Risk of bias across studies · hedged
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“Final quality of evidence was lower for lidocaine patches and BTX-A.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
plain- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 19
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“The systematic review of the literature compiled with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements.22”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Procedures
What the sources say
- Supportedcites [22] Moher, 2009, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med source
The PRISMA Statement section identifies PRISMA as a 27-item checklist and four-phase flow diagram for reporting systematic reviews. The citation identifies the reporting standard the citing authors say they followed; it does not serve as an independent audit of their review. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
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“Tolerability/safety and values/preferences were high for lidocaine patches and lower for opioids and TCAs.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Findings
plaincorrelational- Asserted: passes — The authors put it forward as true.
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“Fifty-five percent of the trials were conducted in diabetic painful polyneuropathy or postherpetic neuralgia.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Study selection and characteristics
plain- Asserted: passes — The authors put it forward as true.
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“Here, we found that high-concentration capsaicin patches were the most susceptible to publication bias, ie, a new study with less than 400 participants with no effect may increase the NNT to an unacceptable level.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“We identified 13 trials of strong opioids using mainly oxycodone (10–120 mg/day) and morphine (90–240mg/day) in peripheral neuropathic pain. The final quality of evidence was moderate. Ten trials were positive: combined NNT was 4·3 (3·4–5·8) and NNH was 11·7 (8·4–19·3).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plain- Asserted: passes — The authors put it forward as true.
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“The trim and fill method suggested 34 theoretical missing studies (figure 3c) and adjusted our effect size from an OR of 1·8 (95% CI 1·7–1·9) to 1·6 (95% CI 1·5–1·7).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Risk of bias across studies
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It was lower (average 3–4) for older studies of TCAs and capsaicin and higher (average >4) for more recent studies (pregabalin, gabapentin, SNRIs, opioids, capsaicin high-concentration patches).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Risk of bias in individual trials
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Long-term controlled studies were lacking and few lasted longer than 12 weeks, with the longest lasting 24 weeks.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Topiramate, zonisamide, and oxcarbazepine/carbamazepine had the poorest safety profile, with combined NNH of 6·3 (5·1–8·0), 2·0 (1·3–4·6), and 5·5 (4·3–7·9), respectively.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We identified 14 RCTs of gabapentin (900–3600 mg/day) (nine positive) and 6 RCTs of gabapentin ER or gabapentin enacarbil (1200–3600 mg/day) (four positive).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We identified one negative study and one positive enrichment study of tapentadol ER: the latter had potential bias (probable unblinding of the patients enrolled in the double blind period) and high NNT (in 67 % of the patients responding to the open phase).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
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In the paper
“There was no evidence for a dose-response effect.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
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In the paper
“A total of 18 out of 25 placebo-controlled RCTs of pregabalin (150–600 mg/day) were positive, with high final quality of evidence.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plain- Asserted: passes — The authors put it forward as true.
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“All seven studies of tramadol (mainly tramadol ER up to 400 mg daily) were positive, with moderate final quality of evidence. Combined NNT was 4·7 (3·6–6·7), with the highest NNT (6·4) in the largest study. Combined NNH was 12·6 (8·4–25·3).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Five out of seven studies (in postherpetic neuralgia or HIV-related painful polyneuropathy) reported sustained efficacy of a single application of high-concentration capsaicin patch (8%)”
- Also stated in: § Quantitative data for individual drugs or drug classes · plain
“The final quality of evidence was high. Combined NNT was 10·6 (7·4–19).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A total of 165 published or unpublished trials with dichotomous data were analysed for publication bias.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Risk of bias across studies
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“we identified only one small negative study of 5% lidocaine patches in postsurgical neuropathic pain and two enriched enrolment studies in postherpetic neuralgia. The smaller study (32 patients) was positive, the larger study (263 patients) was negative in the ITT population, but positive in the per protocol population.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
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In the paper
“Six RCTs evaluated the efficacy of a single administration of BTX-A (50–200 units subcutaneously in the painful area) in peripheral neuropathic pain. The smaller studies had a positive primary outcome (NNT of 1·9 (1·5–2·4) for four studies) with a very low placebo effect, but one large unpublished study was negative.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Safety was good (NNH 25·6 (15·3–78·6) for gabapentin and 31·9 (17·1–230) for gabapentin ER).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Few relevant trials appeared since our meta-analysis, but none affected the recommendations (appendix 11).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > GRADE recommendations
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Results of quantitative data for individual drugs, showing NNT for 50 % pain relief ranging from around 4 to 10 across most positive trials, emphasizes the overall modest study outcomes in neuropathic pain.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Of seven RCTs of various combination therapy in neuropathic pain (appendices 4 and 6), two found that gabapentin combined to morphine or to nortriptyline was superior to monotherapy (and to placebo in one study) at reduced dosages and with no more side effects.”
- Also stated in: § Combination therapy · plain
“However the largest study (not placebo controlled) showed no difference in efficacy or side effects between pregabalin combined to duloxetine at moderate dosages (300 mg pregabalin, 60 mg duloxetine daily) and monotherapy at high dosages (600 mg pregabalin, 120 mg duloxetine daily) in patients not responsive to monotherapy at moderate dosages.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Combination therapy
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Maximum effectiveness seemed associated with 180 mg morphine or equivalent (no additional benefit for higher doses).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Quantitative data for individual drugs or drug classes
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Limited efficacy, large placebo responses, inadequate diagnostic criteria and poor phenotypic profiling probably account for modest trial outcomes and should be taken into account in future studies.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Abstract > Interpretation
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Adequate diagnostic criteria for neuropathic pain are lacking.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We used a standardized review and data extraction protocol (unpublished, appendices 2 and 3).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The GRADE classification was used to assess recommendations based on a group of RCTs pertaining to the same drug or drug class when relevant (ie TCAs)17,18 with final quality of evidence rated as strong or weak for the treatment, against the treatment, or inconclusive”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Evidence summary and reporting
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Studies were assessed for methodological quality using the five-point Oxford Quality Scale25 by two independent authors (appendix 1).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Procedures
What the sources say
- Not checked yetcites [25] Jadad, 1996, Assessing the quality of reports of randomized clinical trials: is blinding necessary?, Control Clin Trials source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Here, a minimum score of 2 out of 5 (randomised and double-blind study) was required for inclusion.25”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Procedures
What the sources say
- Not checked yetcites [25] Jadad, 1996, Assessing the quality of reports of randomized clinical trials: is blinding necessary?, Control Clin Trials source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was introduced in 200017,18 and has received widespread international acceptance.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Introduction
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We also assessed serious risk of bias relating to lack of allocation concealment, incomplete accounting of outcome events, selective outcome reporting, stopping early for benefit, use of invalidated outcome measures and carryover effects in crossover trials.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Procedures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“An assessment of publication bias was performed using funnel plots,26 Egger’s regression,27 and Duval and Tweedie’s non-parametric trim and fill approach.28”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Statistics
What the sources say
- Not checked yetcites [26] Light, 1984
- Not checked yetcites [27] Egger, 1997, Bias in meta-analysis detected by a simple, graphical test, BMJ source
- Not checked yetcites [28] Duval, 2000, Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis, Biometrics source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The extent to which the observed variability (heterogeneity) in treatment effects is explained by publication in a peer-reviewed journal was assessed using meta-regression.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Statistics
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Additionally, we estimated the susceptibility to bias for individual drug classes.29,30”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Methods > Statistics
What the sources say
- Not checked yetcites [29] Moore, 2008, Managing potential publication bias
- Not checked yetcites [30] Moore, 2011, Single dose oral analgesics for acute postoperative pain in adults, Cochrane Database Syst Rev source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This may be due to lack of diagnostic accuracy and relatively ineffective drugs, but also insufficient knowledge about effective drugs and their appropriate use in clinical practice.8”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Introduction
What the sources say
- Not checked yetcites [8] Martinez, 2014, Adherence of French GPs to Chronic Neuropathic Pain Clinical Guidelines: Results of a Cross-Sectional, Randomized, “e” Case-Vignette Survey, PLoS One source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, they may not be applicable for trigeminal neuralgia, for which we could extract only one study complying with our inclusion criteria.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > GRADE recommendations
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This may be due to large placebo responses in HIV-related neuropathy trials,45 a distinct clinical phenotype in subgroups of patients with radiculopathy,46 or psychological/psychosocial comorbidites, often neglected in large trials.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, none of the studies assessed pediatric neuropathic pain, and the present guidelines therefore only apply to adults.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > GRADE recommendations
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Publication bias may be present if studies with positive results are published while those with no data or negative results are not.29 It may lead to major overestimation of efficacy in therapeutic studies.47”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [29] Moore, 2008, Managing potential publication bias
- Not checked yetcites [47] Thornton, 2000, Publication bias in meta-analysis: its causes and consequences, J Clin Epidemiol source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similarly these recommendations do not apply to acute pain or acute pain exacerbation.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > GRADE recommendations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Side effects may, however, to some degree depend on the aetiology, eg, drugs with CNS-related side effects may be less tolerated in patients with CNS lesions.44”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [44] Cepeda, 2012, Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis, Pain Med source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was generally no evidence for efficacy of particular drugs in specific conditions. Therefore these recommendations apply to neuropathic pain in general.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > GRADE recommendations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Few studies included cancer-related neuropathic pain; the recommendations for the use of opioids may be different in certain cancer populations.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > GRADE recommendations
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Inadequate response of neuropathic pain to drug therapy constitutes a highly unmet need and may have substantial consequences in terms of psychological or social adjustment.49”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [49] Treede, 2008, Neuropathic pain: redefinition and a grading system for clinical and research purposes, Neurology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither individual studies nor their statistical combination demonstrated significant differences in efficacy or safety between drugs. Despite limited sample sizes and unknown assay sensitivity in the lack of placebo groups, results suggest comparable efficacy across first- and most second-line recommended treatments.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Results > Comparative drug trials
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This supports the robustness of a meta-analysis taking into account unpublished trials, and suggests that effect sizes were overestimated in previous meta-analyses of pharmacotherapy for neuropathic pain.”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It has recently been reported that the drug treatment of postherpetic neuralgia by primary care physicians was roughly consistent with the US recommendations issued some years before.6”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [6] Dworkin, 2012, Is treatment of postherpetic neuralgia in the community consistent with evidence-based recommendations?, Pain source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“One major issue is the placebo response which seems to have increased in recent trials of neuropathic pain and may lead to an underestimation of drug effects.51”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [51] Demant, 2014, The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study, Pain source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“We provide a weak recommendation against the use of cannabinoids in neuropathic pain, mainly because of negative results, potential misuse, abuse, diversion and long term mental health risks particularly in susceptible individuals.66–71”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [66] Di, 2009, High-potency cannabis and the risk of psychosis, Br J Psychiatry source
- Not checked yetcites [67] Kuepper, 2011, Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study, BMJ source
- Not checked yetcites [68] Hall, 2011, Cannabis and the increased incidence and persistence of psychosis, BMJ source
- Not checked yetcites [69] Davis, 2013, Association between cannabis use, psychosis, and schizotypal personality disorder: findings from the National Epidemiologic Survey on Alcohol and Related Conditions, Schizophr Res source
- Not checked yetcites [70] Gilman, 2014, Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users, J Neurosci source
- Not checked yetcites [71]
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The use of diagnostic algorithms for neuropathic pain53 and screening tools54 should contribute to reducing diagnostic heterogeneity (Table 4).”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [53] Bouhassira, 2014, Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the randomized, double-blind, COMBO-DN study, Pain source
- Not checked yetcites [54] Farrar, 2014, Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: an ACTTION study, Pain source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Adequate diagnostic criteria for neuropathic pain are lacking.
In the paper
“Capsaicin patches are proposed as second-line for peripheral neuropathic pain because of high quality of evidence, but modest effect size, training requirements, and potential safety concerns on sensation with long-term use.65”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [65] Semple, 2005, Cannabis as a risk factor for psychosis: systematic review, J Psychopharmacol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lastly, a largely debated issue concerns the heterogeneity of patient phenotypes in clinical trials, which may reflect various underlying mechanisms.55–57”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
- Not checked yetcites [55] Dworkin, 2013, Assay sensitivity and study features in neuropathic pain trials: an ACTTION meta-analysis, Neurology source
- Not checked yetcites [56] Lund, 2014, Randomised controlled trials may underestimate drug effects: balanced placebo trial design, PLoS One source
- Not checked yetcites [57] Attal, 2011, Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome?, Eur J Pain source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Placebo response has been found to be higher in HIV-related neuropathies,45 and in patients with low or variable pain scores at inclusion.52 Conversely it seems to be lower in postherpetic neuralgia.45”
§ Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations > Discussion
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Neuropathic pain is hard to treat.
“Neuropathic pain is difficult to treat.”
The paper relies on this without support.
Large unpublished trials that were previously hidden can now be found on clinicaltrials.gov and pharmaceutical industry websites.
“Previously hidden and unpublished large trials can now be identified on the web (clinicaltrials.gov, pharmaceutical industry websites)”
The paper relies on this without support.
Topical agents are not known to be relevant for central neuropathic pain.
“Topical agents have no known relevance for use in central neuropathic pain, and this is clearly stated in our recommendations.”
The paper relies on this without support.
Adequate diagnostic criteria for neuropathic pain are lacking.
“Another issue concerns the lack of adequate diagnostic criteria for neuropathic pain (available on request for individual trials).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, medical treatment comes with many side effects [5].”
From Virtual walking therapy in neuropathic spinal cord injury pain: a feasibility study (2024) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent reviews conclude that there is a lack of evidence for the impact of pharmacological and non-pharmacological treatments [5].”
From Virtual walking therapy in neuropathic spinal cord injury pain: a feasibility study (2024) · cites this paper as [5]
Experimental — accuracy not yet measured
Citations
Cites
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & for the PRISMA Group (2009) · BMJ · doi:10.1136/bmj.b2535 · Cited by 83,823
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement
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Bias in meta-analysis detected by a simple, graphical test
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GRADE: an emerging consensus on rating quality of evidence and strength of recommendations
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Assessing the quality of reports of randomized clinical trials: Is blinding necessary?
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Cited by
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Items 501–600 of 1,007
The Role of Biofactors in Diabetic Microvascular Complications
Ziegler, D., Porta, M., Παπάνας, Ν., Moța, M., Jermendy, G., Beltramo, E., Mazzeo, A., Caccioppo, A., Striglia, E., Serhiyenko, V. A., et al. (2021) · Current Diabetes Reviews · doi:10.2174/1871527320666210825112240 · Cited by 58
Stress/cell death pathways, neuroinflammation, and neuropathic pain
Li, L., Li, T. X., Qu, X., Sun, G., Fu, Q., & Han, G. (2023) · Immunological Reviews · doi:10.1111/imr.13275 · Cited by 57
Tiwari, V., Yang, F., He, S.-Q., Shechter, R., Zhang, C., Shu, B., Zhang, T., Tiwari, V., Wang, Y., Dong, X., et al. (2016) · Anesthesiology · doi:10.1097/aln.0000000000000993 · Cited by 55
Self-citationDifferential expression of P2X7 receptor and IL-1β in nociceptive and neuropathic pain
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Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics
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Capsaicin 8% dermal patch in clinical practice: an expert opinion
Bonezzi, C., Costantini, A., Cruccu, G., Fornasari, D., Guardamagna, V. A., Palmieri, V., Polati, E., Zini, P., & Dickenson, A. H. (2020) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2020.1759550 · Cited by 59
Rice, A. S. C., Dworkin, R. H., Finnerup, N. B., Attal, N., Anand, P., Freeman, R. L., Piaia, A., Callegari, F., Doerr, C., Mondal, S., et al. (2021) · Pain · doi:10.1097/j.pain.0000000000002252 · Cited by 55
Self-citationPrevalence and associated factors of pain in the Swiss spinal cord injury population
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Diabetes mellitus type 2 in adults
Dedov, I. I., Shestakova, M. V., Mayorov, A. Y., Шамхалова, М. Ш., Sukhareva, O. Y., Galstyan, G. R., Tokmakova, A. Y., Nikonova, T. V., Surkova, E. V., Кононенко, И. В., et al. (2020) · Diabetes Mellitus · doi:10.14341/dm12507 · Cited by 60
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Long-Term Outcome of the Management of Chronic Neuropathic Pain: A Prospective Observational Study
Moulin, D. E., Clark, A. J., GORDON, A. S., Lynch, M. E., Morley-Forster, P., Nathan, H., Smyth, C., Toth, C. C., VanDenKerkhof, E. G., Gilani, A. A., et al. (2015) · Journal of Pain · doi:10.1016/j.jpain.2015.05.011 · Cited by 54
Placebo, nocebo, and neuropathic pain
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Metadata
- Authors
- Finnerup, N. B., Attal, N., Haroutounian, S., McNicol, E., Baron, R., Dworkin, R. H., Gilron, I., Haanpää, M., Hansson, P., Jensen, T. S., Kamerman, P. R., Lund, K., Moore, A., Raja, S. N., Rice, A. S. C., Rowbotham, M., Sena, E., Siddall, P., Smith, B. H., & Wallace, M.
- Affiliations
- Aarhus University (DK)
- Inserm (FR)
- Washington University in St. Louis (US)
- Tufts Medical Center (US)
- University Hospital Schleswig-Holstein (DE)
- University of Rochester Medicine (US)
- Queen's University (CA)
- Helsinki University Hospital (FI)
- Oslo University Hospital (NO)
- University of the Witwatersrand (ZA)
- Churchill Hospital (GB)
- Johns Hopkins University (US)
- Chelsea and Westminster Hospital NHS Foundation Trust (GB)
- University of California, San Francisco (US)
- Florey Institute of Neuroscience and Mental Health (AU)
- The University of Sydney (AU)
- University of Dundee (GB)
- University of California San Diego (US)
- Corresponding author
- Attal, Nadine
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 14
- Issue
- 2
- Pages
- 162-173
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC4493167
- OpenAlex
- W2104818454
- Cited by
- 3,980
- References
- 80
- Citations by year
- 2026: 316 · 2025: 363 · 2024: 399 · 2023: 362 · 2022: 367 · 2021: 447 · 2020: 384 · 2019: 367 · 2018: 336 · 2017: 305 · 2016: 228 · 2015: 99
- FWCI
- 39.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Medtronic
- Sanofi Pasteur
- Advanced Scientific Computing Research
- Dunhill Medical Trust
- National Institutes of Health
- Biogen Idec
- Deutsche Forschungsgemeinschaft
- U.S. Food and Drug Administration
- AbbVie
- National Institute of Academic Anaesthesia
- Novartis
- International Fibrodysplasia Ossificans Progressiva Association
- Pfizer
- Merck Sharp and Dohme
- National Centre for the Replacement Refinement and Reduction of Animals in Research
- Astellas Pharma US
- Wellcome Trust
- AstraZeneca
- Westminster Medical School Research Trust
- Merck
- Bundesministerium für Bildung und Forschung
- Allergan
- Eisai
- Eli Lilly and Company
- Boehringer Ingelheim
- Bayer Schering
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- neuropathic pain, pharmacotherapy, duloxetine, pregabalin, gabapentin, tricyclic antidepressants, tramadol, botulinum toxin type A, lidocaine patch, capsaicin patch, topical analgesics, number needed to treat, publication bias, treatment guidelines, first-line therapy, safety and tolerability, cost-effectiveness, adults, quality of evidence
- MeSH terms
- Adult, Analgesics, Opioid, Antidepressive Agents, Tricyclic, Humans, Neuralgia, Randomized Controlled Trials as Topic, Pain Management
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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