Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis

May combine two claims.

Tolerability/safety and values/preferences were high for lidocaine patches and lower for opioids and tricyclic antidepressants.

“Tolerability/safety and values/preferences were high for lidocaine patches and lower for opioids and TCAs.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Fifty-five percent of the trials were in diabetic painful polyneuropathy or postherpetic neuralgia.

“Fifty-five percent of the trials were conducted in diabetic painful polyneuropathy or postherpetic neuralgia.”

May combine two claims.

High-concentration capsaicin patches were most susceptible to publication bias; a new no-effect study with fewer than 400 participants could raise the NNT to an unacceptable level.

“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.”

May combine two claims.

Thirteen strong-opioid trials were identified; final quality was moderate, ten trials were positive, combined NNT was 4.3 and NNH was 11.7.

“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).”

May combine two claims.

Trim-and-fill analysis suggested 34 missing studies and adjusted the effect size from an OR of 1.8 to 1.6.

“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).”

May combine two claims.

Oxford quality scores were lower for older TCA and capsaicin studies and higher for more recent pregabalin, gabapentin, SNRI, opioid, and capsaicin high-concentration patch studies.

“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).”

May combine two claims.

Long-term controlled studies were lacking; few lasted longer than 12 weeks, and the longest lasted 24 weeks.

“Long-term controlled studies were lacking and few lasted longer than 12 weeks, with the longest lasting 24 weeks.”

May combine two claims.

Topiramate, zonisamide, and oxcarbazepine/carbamazepine had the poorest safety profiles, with combined NNHs of 6.3, 2.0, and 5.5.

“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.”

May combine two claims.

There were 14 gabapentin RCTs (nine positive) and 6 gabapentin ER or enacarbil RCTs (four positive).

“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).”

May combine two claims.

For tapentadol ER, one study was negative and one positive enrichment study had potential bias and a high NNT.

“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).”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

There was no evidence of a dose-response effect for gabapentin.

“There was no evidence for a dose-response effect.”

May combine two claims.

Eighteen of 25 placebo-controlled pregabalin trials were positive, with high final quality of evidence.

“A total of 18 out of 25 placebo-controlled RCTs of pregabalin (150–600 mg/day) were positive, with high final quality of evidence.”

May combine two claims.

All seven tramadol studies were positive, with moderate final quality of evidence; combined NNT was 4.7 and NNH was 12.6.

“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).”

May combine two claims.

Five of seven studies reported sustained efficacy of a single high-concentration capsaicin patch; final quality was high, and combined NNT was 10.6.

“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).”

Classified as probably not a substantial claim.

A total of 165 published or unpublished trials with dichotomous data were analysed for publication bias.

“A total of 165 published or unpublished trials with dichotomous data were analysed for publication bias.”

May combine two claims.

For 5% lidocaine patches, one small postsurgical study was negative and two enriched-enrolment postherpetic neuralgia studies were identified; the smaller was positive, while the larger was negative in the ITT population but positive per protocol.

“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.”

May combine two claims.

Six BTX-A RCTs were identified; smaller studies had a positive primary outcome with NNT 1.9, but one large unpublished study was negative.

“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.”

May combine two claims.

Safety was good, with NNH 25.6 for gabapentin and 31.9 for gabapentin ER.

“Safety was good (NNH 25·6 (15·3–78·6) for gabapentin and 31·9 (17·1–230) for gabapentin ER).”

May combine two claims.

Few relevant trials appeared after the meta-analysis, and none changed the recommendations.

“Few relevant trials appeared since our meta-analysis, but none affected the recommendations (appendix 11).”

May combine two claims.

NNTs for 50% pain relief ranged from about 4 to 10 across most positive trials, emphasizing generally modest outcomes in neuropathic pain.

“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.”

May combine two claims.

Among seven combination-therapy RCTs, two found gabapentin combined with morphine or nortriptyline superior to monotherapy at reduced dosages with no more side effects, while the largest study found no difference between pregabalin plus duloxetine and monotherapy.

“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.”

May combine two claims.

Maximum effectiveness of strong opioids seemed to occur at 180 mg morphine equivalent, with no additional benefit at higher doses.

“Maximum effectiveness seemed associated with 180 mg morphine or equivalent (no additional benefit for higher doses).”

May combine two claims.

Limited efficacy, large placebo responses, inadequate diagnostic criteria and poor phenotypic profiling probably explain the modest trial outcomes.

“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.”

• AssumptionRests on an assumption: Adequate diagnostic criteria for neuropathic pain are lacking.

Classified as probably not a substantial claim.

A standardized review and data extraction protocol was used.

“We used a standardized review and data extraction protocol (unpublished, appendices 2 and 3).”

Classified as probably not a substantial claim. May combine two claims.

GRADE was used to assess recommendations and to rate final quality of evidence as strong or weak for, against, or inconclusive about treatment.

“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”

• cites [17] Guyatt, 2008, GRADE: an emerging consensus on rating quality of evidence and strength of recommendations, BMJ sourceNot checked yet

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• cites [18] Balshem, 2011, GRADE guidelines: 3. Rating the quality of evidence, J Clin Epidemiol sourceNot checked yet

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Classified as probably not a substantial claim.

Methodological quality was assessed with the five-point Oxford Quality Scale by two independent authors.

“Studies were assessed for methodological quality using the five-point Oxford Quality Scale25 by two independent authors (appendix 1).”

• cites [25] Jadad, 1996, Assessing the quality of reports of randomized clinical trials: is blinding necessary?, Control Clin Trials sourceNot checked yet

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Classified as probably not a substantial claim.

A minimum Oxford Quality Score of 2 out of 5 was required for inclusion.

“Here, a minimum score of 2 out of 5 (randomised and double-blind study) was required for inclusion.25”

• cites [25] Jadad, 1996, Assessing the quality of reports of randomized clinical trials: is blinding necessary?, Control Clin Trials sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

GRADE was introduced in 2000 and has gained widespread international acceptance.

“the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was introduced in 200017,18 and has received widespread international acceptance.”

• cites [17] Guyatt, 2008, GRADE: an emerging consensus on rating quality of evidence and strength of recommendations, BMJ sourceNot checked yet

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• cites [18] Balshem, 2011, GRADE guidelines: 3. Rating the quality of evidence, J Clin Epidemiol sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Serious risk of bias was assessed for allocation concealment, incomplete outcome accounting, selective outcome reporting, early stopping for benefit, invalidated outcome measures, and carryover effects in crossover trials.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Publication bias was assessed using funnel plots, Egger's regression, and Duval and Tweedie's trim-and-fill method.

“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”

• cites [26] Light, 1984Not checked yet

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• cites [27] Egger, 1997, Bias in meta-analysis detected by a simple, graphical test, BMJ sourceNot checked yet

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• cites [28] Duval, 2000, Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis, Biometrics sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Meta-regression was used to assess how much variability in treatment effects was explained by publication in a peer-reviewed journal.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The systematic review complied with the PRISMA statements.

“The systematic review of the literature compiled with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements.22”

• cites [22] Moher, 2009, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Susceptibility to bias was estimated for individual drug classes.

“Additionally, we estimated the susceptibility to bias for individual drug classes.29,30”

• cites [29] Moore, 2008, Managing potential publication biasNot checked yet

  Not checked in the free run.

• cites [30] Moore, 2011, Single dose oral analgesics for acute postoperative pain in adults, Cochrane Database Syst Rev sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Undertreatment of neuropathic pain may be due to lack of diagnostic accuracy, relatively ineffective drugs, and insufficient knowledge about effective drugs and their appropriate use.

“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”

• cites [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 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The recommendations may not apply to trigeminal neuralgia, for which only one eligible study was found.

“However, they may not be applicable for trigeminal neuralgia, for which we could extract only one study complying with our inclusion criteria.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The greater refractoriness of HIV-related neuropathy and radiculopathy may be due to large placebo responses, a distinct clinical phenotype, or neglected psychosocial comorbidities.

“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.”

• cites [45] Mahn, 2011, Sensory symptom profiles and co-morbidities in painful radiculopathy, PLoS One sourceNot checked yet

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• cites [46] Sena, 2010, Publication bias in reports of animal stroke studies leads to major overstatement of efficacy, PLoS Biol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

No studies assessed pediatric neuropathic pain, so the guidelines apply only to adults.

“However, none of the studies assessed pediatric neuropathic pain, and the present guidelines therefore only apply to adults.”

May combine two claims.

Publication bias can occur when positive studies are published and negative or no-data studies are not, and it can greatly overestimate efficacy in therapeutic studies.

“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”

• cites [29] Moore, 2008, Managing potential publication biasNot checked yet

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• cites [47] Thornton, 2000, Publication bias in meta-analysis: its causes and consequences, J Clin Epidemiol sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The recommendations do not apply to acute pain or acute pain exacerbation.

“Similarly these recommendations do not apply to acute pain or acute pain exacerbation.”

May combine two claims.

Side effects may to some degree depend on aetiology; for example, drugs with CNS-related side effects may be less tolerated in patients with CNS lesions.

“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”

• cites [44] Cepeda, 2012, Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis, Pain Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Because there was generally no evidence that particular drugs work in specific conditions, the recommendations apply to neuropathic pain in general.

“There was generally no evidence for efficacy of particular drugs in specific conditions. Therefore these recommendations apply to neuropathic pain in general.”

May combine two claims.

Few studies included cancer-related neuropathic pain, so opioid recommendations may differ in some cancer populations.

“Few studies included cancer-related neuropathic pain; the recommendations for the use of opioids may be different in certain cancer populations.”

May combine two claims.

Inadequate response of neuropathic pain to drug therapy is a major unmet need and may have substantial psychological or social consequences.

“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”

• cites [49] Treede, 2008, Neuropathic pain: redefinition and a grading system for clinical and research purposes, Neurology sourceNot checked yet

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May combine two claims.

Comparative RCTs showed no significant differences in efficacy or safety between drugs, and results suggest comparable efficacy across first-line and most second-line recommended treatments.

“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.”

May combine two claims.

This supports the robustness of a meta-analysis that includes unpublished trials and suggests that earlier meta-analyses of neuropathic pain pharmacotherapy overestimated effect sizes.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Primary care physicians' drug treatment of postherpetic neuralgia was recently reported to be roughly consistent with earlier US recommendations.

“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”

• cites [6] Dworkin, 2012, Is treatment of postherpetic neuralgia in the community consistent with evidence-based recommendations?, Pain sourceNot checked yet

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May combine two claims.

Placebo response seems to have increased in recent neuropathic pain trials and may lead to underestimation of drug effects.

“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”

• cites [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 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

The paper gives a weak recommendation against cannabinoids in neuropathic pain, mainly because of negative results and risks of misuse, abuse, diversion, and long-term mental health harm in susceptible people.

“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”

• cites [66] Di, 2009, High-potency cannabis and the risk of psychosis, Br J Psychiatry sourceNot checked yet

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• cites [67] Kuepper, 2011, Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study, BMJ sourceNot checked yet

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• cites [68] Hall, 2011, Cannabis and the increased incidence and persistence of psychosis, BMJ sourceNot checked yet

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• cites [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 sourceNot checked yet

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• cites [70] Gilman, 2014, Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users, J Neurosci sourceNot checked yet

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• cites [71]Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Using diagnostic algorithms and screening tools for neuropathic pain should help reduce diagnostic heterogeneity.

“The use of diagnostic algorithms for neuropathic pain53 and screening tools54 should contribute to reducing diagnostic heterogeneity (Table 4).”

• cites [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 sourceNot checked yet

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• cites [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 sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Adequate diagnostic criteria for neuropathic pain are lacking.

May combine two claims.

Capsaicin patches are proposed as second-line for peripheral neuropathic pain because of high-quality evidence but modest effect size, training requirements, and potential long-term safety concerns about sensation.

“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”

• cites [65] Semple, 2005, Cannabis as a risk factor for psychosis: systematic review, J Psychopharmacol sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Heterogeneity of patient phenotypes in clinical trials may reflect various underlying mechanisms.

“Lastly, a largely debated issue concerns the heterogeneity of patient phenotypes in clinical trials, which may reflect various underlying mechanisms.55–57”

• cites [55] Dworkin, 2013, Assay sensitivity and study features in neuropathic pain trials: an ACTTION meta-analysis, Neurology sourceNot checked yet

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• cites [56] Lund, 2014, Randomised controlled trials may underestimate drug effects: balanced placebo trial design, PLoS One sourceNot checked yet

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• cites [57] Attal, 2011, Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome?, Eur J Pain sourceNot checked yet

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May combine two claims.

Placebo response is higher in HIV-related neuropathies and in patients with low or variable baseline pain scores, and lower in postherpetic neuralgia.

“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”

• cites [45] Mahn, 2011, Sensory symptom profiles and co-morbidities in painful radiculopathy, PLoS One sourceNot checked yet

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• cites [52] Campbell, 2012, Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy, Pain sourceNot checked yet

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