neuropathic pain section

NEUROPATHIC PAIN SECTION

Original Research ArticlePlacebo Response Changes Depending on theNeuropathic Pain Syndrome: Results of aSystematic Review and Meta-Analysispme_1340 575..595

M. Soledad Cepeda, MD, PhD,*Jesse A. Berlin, ScD,* C. Yuying Gao, MD, PhD,†Frank Wiegand, MD, PhD,‡ and D. Russell Wada,PhD†

*Janssen Research and Development, L.L.C.,Titusville, New Jersey;

†Quantitative Solutions, Inc., Menlo Park, California;

‡Janssen Global Services L.L.C., Raritan, New Jersey,USA

Reprint requests to: M. Soledad Cepeda, MD, PhD,Janssen Research and Development, L.L.C., 1125Trenton Harbourton Road, Office: E30001, Titusville,NJ 08560, USA. Tel: 609-730-2413; Fax:609-730-7927; E-mail: [email protected].

Financial disclosure: M. Soledad Cepeda and JesseBerlin are employees of Janssen PharmaceuticalResearch & Development, LLC. JanssenPharmaceutical Research & Development, LLC is anaffiliate of Ortho-McNeil-Janssen Pharmaceuticals,Inc, which markets several analgesic drug productsincluding opioids and over-the-counter analgesics.Frank Wiegand is an employee and shareholder ofJanssen Global Services LLC. During the conduct ofthe work described herein; C. Yuying Gao and D.Russell Wada were paid consultants to JanssenPharmaceutical Research & Development.

Abstract

Objective. To compare placebo responses inneuropathic pain syndromes.

Design. Systematic literature review and meta-analysis.

Setting and Patients. Randomized placebo-controlled trials assessing pain intensity or painrelief in any neuropathic pain syndrome publishedsince 1995 with �5 days follow-up.

Interventions. Placebo response.

Outcome Measures. Pain intensity and responderrates (proportion reporting �50% pain relief). Meta-regression models were built.

Results. Ninety-four studies (N = 5,317) wereincluded in the pain intensity analysis; 47 studies(N = 3,087) were included in the responder analysis.After controlling for potential confounders (e.g.,subject characteristics, study design characteris-tics), the placebo response was found to be largeand varied with the pain syndrome. Compared withdiabetic neuropathic/polyneuropathic pain (DPN),the placebo response for a decline in pain intensityand responder rate was smaller in trials thatassessed central pain and postherpetic neuralgia(PHN) and larger in trials that assessed HIV pain.The model-predicted mean decrease (95% confi-dence interval [CI]) from baseline in pain intensity(0–10 scale) was as follows: DPN, 1.45 (1.35 to 1.55);PHN, 1.16 (1.03 to 1.29); central pain, 0.44 (-0.41 to1.30); HIV pain, 1.82 (1.51 to 2.12). The predictedresponder rates (95% CI) were as follows: DPN, 20%(14.6 to 25.8); PHN, 11.5% (8.4 to 14.5); central pain,7.2% (2.1 to 12.3); HIV pain, 42.8% (34.9 to 50.7). Thetype of treatment in the active arm also influencedthe placebo response.

Conclusions. Placebo response is influenced bythe pain syndrome evaluated. These differencesshould be considered when evaluating novelcompounds for the treatment of neuropathic painconditions.

Key Words. Placebos; Anticonvulsants; Antide-pressants; NMDA Antagonists; Opioids; Post-Herpetic Neuralgia; Reflex Sympathetic Dystrophy;Risk Factors; Neuropathy

Introduction

A high placebo response has been identified as one of thestrongest factors that lead to failed clinical trials, evenwhen the active treatment has been previously shown tobe effective [1]. A better understanding of the factors thatinfluence placebo response in clinical trials could permitresearchers to design trials that may be more able to

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Pain Medicine 2012; 13: 575–595Wiley Periodicals, Inc.

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detect the benefit of efficacious treatments compared withplacebo.

Evaluations of the placebo response rates in painstudies have revealed that both subject and study char-acteristics may influence the observed response. In termsof subject characteristics, subject expectations are asso-ciated with a placebo response (i.e., the higher a subject’sexpectations, the higher the placebo response) and sub-jects who are highly adherent to the study medicationhave a higher placebo response than non-adherent sub-jects [2,3]. Although subjects with larger fluctuations inpain are more likely to have higher placebo responsesthan subjects with less variability in pain over time [4], theeffect of baseline pain intensity on the placebo response isnot yet clear. Some findings suggest that subjects withhigher baseline pain intensity have a significantly greaterreduction in pain intensity than subjects with lower base-line scores [5] while other findings suggest that the base-line pain intensity has no effect on the placebo response[6]. Gender does not seem to affect the placebo response[7]. In terms of study characteristics, a greater placeboresponse is generally observed in trials with longerfollow-up [8] and larger sample sizes [5], and parallel-group studies seem to have a higher placebo responsethan crossover studies [5].

Recent research suggests that the pain syndromes underevaluation may also affect the placebo response [5,9].Studies evaluating painful diabetic neuropathy have beenfound to have a higher placebo response than studiesevaluating postherpetic neuralgia [8,9]. These findingswere primarily based on an analysis of pain intensityreduction in the placebo arms of 58 studies [9]. The trialsincluded in that analysis assessed diabetic neuropathyand postherpetic neuralgia. Because only two pain syn-dromes and only pain intensity (not the responder rate)were evaluated, a more comprehensive comparison ofthe placebo response in studies evaluating neuropathicpain was conducted for the current analysis, using a sys-tematic review of the literature and meta-analysis of trialsthat assessed pain intensity or responder rates in anyneuropathic pain syndrome.

Methods

Data Sources and Study Selection

A systematic review of English-language articles was per-formed using MEDLINE and the ClinicalTrials.gov registryon November 16, 2010. Search terms included the fol-lowing: randomized controlled trial, diabetic neuropathy,postherpetic neuralgia, neuropath*, or neuralg*, carpaltunnel syndrome, phantom, postamputation, central pain,complex regional pain, trigeminal, reflex sympatheticdystrophy, polyneuropathy, postmastectomy, and post-thoracotomy. The search strategy used is described inAppendix 1.

Included studies were randomized, placebo-controlled,parallel-group or crossover studies published in 1995 or

later with at least 5 days of treatment exposure or follow-upthat reported pain intensity (on a 0–10 or a 0–100 scale) orresponder rate. Open-label studies were excluded.

The following information was extracted from each study:mean age; percentage of participants who were male;sample size; whether the study was parallel or crossover;number of arms; year of completion of the study; studydesign, conduct, and reporting information (was thestudy described as double-blind?, was the randomiza-tion scheme described?, was the allocation sequenceconcealed?, and was there a description of dropoutsand withdrawals?); treatment information (treatment drugclass) and route of administration; duration of follow-up;type of pain syndrome; mean pain intensity at baseline, atthe end of treatment, and mean change from baseline;and responder rate data, all in the placebo group only, andthe corresponding measures of variability.

Data Synthesis

Scales from 0 to 100 were converted to 0 to10.For crossover studies, only data from the first periodwere used, treating this first period as a parallel-groupcomparison.

To compare the placebo response in the variousneuropathic pain syndromes and to explain hetero-geneity of results among studies, random-effects meta-regression models were built, one for pain intensity andanother for responder rate (proportion of subjects whoreported at least 50% pain relief vs baseline pain intensity).Random-effects meta-regression is recommended overfixed-effects meta-regression because fixed-effects meta-regression leads to excessive false positives results in thepresence of heterogeneity [10].

Pain intensity was analyzed using a linear regressionmodel in two ways: mean final pain intensity and meanchange from baseline. Eighty percent of the studies thatreported mean change from baseline and 50% of the trialsthat reported mean final pain intensity did not report ameasure of dispersion. The standard deviations wereimputed using the average of the standard deviations ofthe trials that reported it [11]. The results of both analyseswere almost identical; the difference consisted in a slightlywider confidence interval in the change from baselineanalysis. Because the change from baseline is easier tointerpret, the results of that analysis are presented.

The various pain syndromes were grouped into the follow-ing categories: cancer-related neuropathic pain, centralneuropathic pain (induced by multiple sclerosis, spinalcord injury, stroke), diabetic neuropathic/polyneuropathicpain, human immunodeficiency virus (HIV)-associatedneuropathic pain, postherpetic neuralgia, phantom pain,posttraumatic/postsurgical/complex regional pain syn-drome (CRPS) pain, and neuropathic pain (when a mixtureof neuropathic pain syndromes was included in the trialand results were not reported separately).

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Because individuals’ expectations of treatment efficacycould affect the placebo response, the type of treatmentclass evaluated in the trial and the route of administrationwere included in the analysis. The treatments weregrouped into the following categories: opioids (e.g., mor-phine), antidepressants (e.g., amitriptyline), anticonvul-sants (e.g., gabapentin), sodium channel blockers (e.g.,lidocaine), N-methyl d-aspartate (NMDA) antagonists(e.g., ketamine), cannabinoids (e.g., sativex), combination(when the trial evaluated more than one of the aboveclasses), and nontraditional (to include miscellaneousmedications such as clodronate and levodopa). The routeof administration was grouped into intravenous and non-intravenous. Because subject characteristics and studydesign characteristics can affect the placebo response,the models also included the pain syndrome, mean base-line pain intensity, year of completion of the study, meanage of subjects in the trial, percentage of males in the trial,treatment duration of the trial, number of arms in the trial,treatment class in the active control group, whether infor-mation regarding dropouts was reported, and whether theplacebo was an “active placebo” (i.e., a placebo thatmimics the adverse effects of the experimental drug).

For the responder rate, the percentage of subjects whoreported at least 50% pain relief was analyzed because 47trials assessed this outcome compared with 34 trials thatevaluated the percentage of subjects who reported atleast 30% pain relief. Responder rate was treated as acontinuous outcome. To allow analyses of studies withzero events (i.e., in which none of the subjects reported�50% pain relief) and calculate approximate standarderrors, we added a constant—1/number of subjects in theplacebo arm to such studies. This is similar, in principle, toadding a continuity correction to studies with no events inone arm to calculate odds ratios or relative risk in meta-analysis. We used the reciprocal of the number of subjectsin the placebo group because this continuity correction isthe one that has been shown to exhibit less bias in meta-analysis of rare events [12], although that finding strictlyapplies to situations in which two treatment groups arebeing compared.

Because the number of studies that reported responderrate was fewer than the studies that reported pain inten-sity, the meta-regression model for responder rateincluded fewer covariates—active treatment assessed inthe active arm, age, baseline pain intensity and year ofpublication of the study.

Diabetic neuropathic/polyneuropathic pain and anticon-vulsants were used as the “reference” groups in theregression models because they were the most frequentlyoccurring groups.

After the random-effects meta-regression models werebuilt, we predicted the decrease in pain intensity and theresponder rate adjusted for all the variables in the regres-sion models, using the fitted values from the models. Wethen produced forest plots with the adjusted results usingthe fixed- and random-effects models to combine the

results by pain syndrome. The fixed-effects model givesmore weight to studies with large sample sizes and smallvariances and the random-effects models, by incorporat-ing into the weights the among-study heterogeneity, givesrelatively more weight to smaller studies. The results areidentical in the absence of heterogeneity, and the resultswill generally differ in the presence of heterogeneity. Wecalculated I2 statistics to quantify the heterogeneity. I2 isthe percentage of variation attributable to heterogeneity. I2

values higher than 50% suggest substantial heterogeneity.

The analyses were conducted with STATA version 10.1(StataCorp, College Station, TX, USA) using the“metareg,” “predict,” and “metan” commands.

Results

The searches provided 624 results; 251 full manuscriptswere reviewed and 141 trials met the inclusion criteria witha total of 6,239 subjects. The number of studies screened,assessed for eligibility, and included in the review withreasons for exclusion at each stage, is listed in Figure 1.

The characteristics of included studies are described inTable 1. The mean (standard deviation [SD]) age of sub-jects included in the trials was 57.1 (8.3) years. The meanproportion of males in the studies was 53%. The mean(SD) duration of follow-up of the studies was 7.8(7.0) weeks. The majority of the trials (93%) reported meanbaseline pain intensity, and 33% of the trials reportedresponder rates (Table 2).

The neuropathic pain syndrome most frequently evaluatedwas diabetic neuropathic/polyneuropathic pain (39.6% ofthe trials), and the least frequently evaluated was cancerrelated neuropathic pain (4.0% of the trials; Table 3). Anti-convulsants were the medications most commonlystudied (49.5% of the trials). The type of treatments evalu-ated varied with the pain syndrome evaluated. Forexample, the studies that assessed cancer neuropathicpain more often evaluated anticonvulsants. The studiesthat assessed phantom pain more commonly evaluatedNMDA receptors antagonists (Table 3).

In terms of study design and reporting features, 99.9% ofthe trials were double-blind, reported the scheme of ran-domization, and had the allocation concealed. Thirtypercent of the trials did not describe dropouts or withdraw-als. Therefore, only the description of dropouts and with-drawals variable was included in the regression models.

Pain Intensity

Ninety-four studies were included in the pain intensityanalysis, with a total of 5,317 subjects [13–106]. Themean (SD) baseline pain intensity was 6.3 (1.0). The unad-justed mean (SD) decrease in pain intensity from baselinewas 1.2 (1.0) units. The unadjusted mean decrease in painintensity from baseline for each of the pain syndromes,along with the corresponding number of trials and number

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of subjects included for each of the pain syndromes, canbe seen in Table 4.

After adjusting for potential risk factors, the placeboresponse was statistically significantly smaller in trials thatevaluated central pain, posttraumatic/postsurgical pain/CRPS and postherpetic neuralgia than in the trials thatevaluated diabetic neuropathic/polyneuropathic pain. Onthe other hand, the placebo response was larger in trialsthat assessed HIV-associated neuropathic pain andphantom pain (Table 5).

These findings translate into a predicted placebo-inducedmean decline in pain intensity on a 0 to 10 scale in sub-jects with diabetic neuropathy of 1.45 units (95% confi-dence interval [CI], 1.35 to 1.55), 1.16 units (95% CI, 1.03to1.29) in subjects with postherpetic neuralgia, 0.53 (95%CI, 0.19 to 0.86) in subjects with central neuropathic painand 1.82 units (95% CI, 1.51 to 2.12) in subjects withHIV-associated neuropathic pain using a random effectmodel. The predicted placebo-induced mean decline inpain intensity was similar when the fixed-effects modelwas used to combine the results despite the

heterogeneity, although as expected, the CIs were nar-rower (Figure 2).

In terms of the effect of the type of drug on the placeboresponse, the trials that assessed NMDA blockers had asmaller placebo response (0.87 units smaller [95% CI,0.04 to 1.71]) than the trials that assessed anticonvulsants(Table 5).

Mean baseline pain intensity, mean age, gender, type ofplacebo used, description of dropouts and withdrawals,year of completion of the study and route of administrationdid not affect the placebo response.

Responder Rate

Forty-seven studies were included in the responderrate analysis, with a total of 3,087 subjects [13,15,16,18–22,27,30,31,34,35,38,41–43,48,49,52,53,55–61,64,66–68,70,79,81,84,92,93,95,96,99,100,106–110]. Theproportion of subjects who achieved at least 50% painrelief was on average 17%, but it ranged from 0% to 43%.

Figure 1 Flow of information through the different phases of the systematic review.

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Tab

le1

Cha

ract

eris

tics

ofin

clud

edst

udie

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istr

atio

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tion

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(Sub

ject

sR

ando

miz

ed)

Trea

tmen

t2

(Sub

ject

sR

ando

miz

ed)

Trea

tmen

t3

(Sub

ject

sR

ando

miz

ed)

Trea

tmen

t4

(Sub

ject

sR

ando

miz

ed)

Dou

ble

Blin

dR

ando

miz

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nA

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pria

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lloca

tion

Con

ceal

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nof

Dro

pout

s

Agr

awal

etal

.[3

7]C

ross

over

Ora

lD

PN

Pla

cebo

(24)

Gly

cery

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e(2

4)y

yy

nA

graw

alet

al.

[25]

Par

alle

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ral

DP

NP

lace

bo(2

1)G

lyce

rylt

rinitr

ate

(20)

Val

proa

te(2

0)G

lyce

rylt

rinitr

ate

+va

lpro

ate

(22)

yy

yn

Am

inan

dS

turr

ock

[109

]C

ross

over

Intr

aven

ous

DP

NP

lace

bo(2

0)A

man

tadi

ne(2

0)y

yy

nA

rbai

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dV

idal

[40]

Par

alle

lIn

trav

enou

sC

ance

rne

urop

athi

cpa

in

Pla

cebo

(18)

Tram

adol

(18)

yy

yn

Are

zzo

etal

.[2

7]P

aral

lel

Ora

lD

PN

Pla

cebo

(85)

Pre

gaba

lin(8

2)y

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nA

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[55]

Par

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yy

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6]P

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Ora

lD

PN

Pla

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(81)

Gab

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tin(8

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yy

yB

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[83]

Par

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DP

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16)

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Ben

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7]P

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(89)

Oxc

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[119

]C

ross

over

Ora

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(19)

yy

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etal

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4]P

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lel

Ora

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HN

Pla

cebo

(63)

Tram

adol

(64)

yy

yn

Bre

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etal

.[1

20]

Cro

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ral

Cen

tral

neur

opat

hic

pain

Pla

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(12)

Lam

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(12)

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Car

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l.[6

9]P

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Ora

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ance

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athi

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in

Pla

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(41)

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Che

net

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[18]

Par

alle

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enou

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(20)

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yC

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[26]

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athi

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in

Pla

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(14)

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Chi

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[121

]C

ross

over

Ora

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Pla

cebo

(15)

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n

De

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and

Min

ardi

[78]

Par

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ral

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66)

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[52]

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yy

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[98]

Par

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579


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Tab

le1

Con

tinue

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tion

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ject

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miz

ed)

Trea

tmen

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(Sub

ject

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ando

miz

ed)

Trea

tmen

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(Sub

ject

sR

ando

miz

ed)

Dou

ble

Blin

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miz

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nA

ppro

pria

teA

lloca

tion

Con

ceal

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Fin

neru

pet

al.

[20]

Cro

ssov

erO

ral

Cen

tral

neur

opat

hic

pain

Pla

cebo

(36)

Leve

tirac

etam

(36)

yy

yy

Fre

eman

etal

.[3

8]P

aral

lel

Ora

lD

PN

Pla

cebo

(153

)Tr

amad

ol(1

60)

yy

yy

Fre

ynha

gen

etal

.[5

7]P

aral

lel

Ora

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euro

path

icpa

inP

lace

bo(6

5)P

rega

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(141

)P

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balin

(132

)y

yy

yG

aler

etal

.[1

23]

Cro

ssov

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ral

PH

NP

lace

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9)R

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le(2

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yy

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aler

etal

.[1

23]

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ssov

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ral

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NP

lace

bo(2

6)R

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le(2

6)y

yy

yG

ilron

etal

.[1

24]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Act

ive

plac

ebo

(44)

Gab

apen

tin(4

8)M

orph

ine

(49)

Gab

apen

tin+

mor

phin

e(4

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yy

y

Gim

bele

tal.

[76]

Par

alle

lO

ral

DP

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lace

bo(7

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done

(82)

yy

yy

Gol

dste

inet

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[56]

Par

alle

lO

ral

DP

NP

lace

bo(1

15)

Dul

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(115

)D

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14)

Dul

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(113

)y

yy

yG

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etal

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0]C

ross

over

Ora

lP

osttr

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athi

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in

Pla

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(59)

Gab

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y

Gor

son

etal

.[1

25]

Par

alle

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ral

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(19)

yy

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Gra

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al.

[97]

Par

alle

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ral

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NA

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aceb

o(1

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Am

itrip

tylin

e(1

1)A

mitr

ipty

line

+flu

phen

azin

e(1

2)F

luph

enaz

ine

(13)

yy

yy

Gro

ssko

pfet

al.

[46]

Par

alle

lO

ral

DP

NP

lace

bo(7

0)O

xcar

baze

pine

(71)

yy

yy

Hah

net

al.

[62]

Par

alle

lO

ral

HIV

-ass

ocia

ted

neur

opat

hic

pain

Pla

cebo

(11)

Gab

apen

tin(1

5)y

yy

y

Ham

mac

ket

al.

[80]

Cro

ssov

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ral

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NP

lace

bo(2

5)N

ortr

ipty

line

(26)

yy

yy

Han

naet

al.

[29]

Par

alle

lO

ral

DP

NP

lace

bo(1

69)

Oxy

codo

ne(1

69)

yy

yy

Hau

ptet

al.

[126

]P

aral

lel

Ora

lD

PN

Pla

cebo

(20)

Ben

fotia

min

e(2

0)y

yy

nH

oet

al.

[127

]C

ross

over

Topi

cal

Neu

ropa

thic

pain

Pla

cebo

(35)

Lido

cain

e(3

5)A

mitr

ipty

line

(35)

yy

yn

Ho

etal

.[1

07]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Act

ive

plac

ebo

(18)

Gab

apen

tin(1

8)Tr

amad

ol(1

8)y

yy

y

Hof

fman

etal

.[1

3]P

aral

lel

Ora

lD

PN

Pla

cebo

(135

)P

rega

balin

(271

)y

yy

yH

use

etal

.[1

10]

Cro

ssov

erO

ral

Pha

ntom

limb

pain

Pla

cebo

(12)

Mst

(12)

yy

yn

Irvi

nget

al.

[92]

Par

alle

lO

ral

PH

NP

lace

bo(5

1)G

abap

entin

ER

(52)

Gab

apen

tinE

R(5

5)y

yy

nK

also

etal

.[1

28]

Cro

ssov

erO

ral

Can

cer

neur

opat

hic

pain

Pla

cebo

(20)

Am

itrip

tylin

e(2

0)y

yy

y

Kar

stet

al.

[74]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Pla

cebo

(11)

Ct-

3(1

0)y

yy

yK

autio

etal

.[1

29]

Par

alle

lO

ral

Can

cer

neur

opat

hic

pain

Pla

cebo

(22)

Am

itrip

tylin

e(2

2)y

yy

y

Kem

per

etal

.[1

30]

Cro

ssov

erO

ral

HIV

-ass

ocia

ted

neur

opat

hic

pain

Pla

cebo

(10)

Mex

iletin

e(9

)y

yy

y

Kho

rom

ieta

l.[1

31]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Act

ive

plac

ebo

(40)

Mor

phin

e(4

1)N

ortr

ipty

line

(34)

Mor

phin

e+

nort

ripty

line

(39)

yy

yy

580

Cepeda et al.

Dow


ic.oup.com/painm


Kho

rom

ieta

l.[1

32]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Act

ive

plac

ebo

(42)

Topi

ram

ate

(42)

Na

(42)

yy

yy

Koc

har

etal

.[7

1]P

aral

lel

Ora

lD

PN

Pla

cebo

(21)

Val

proa

te(2

2)y

yy

yK

ocha

ret

al.

[60]

Par

alle

lO

ral

PH

NP

lace

bo(2

2)D

ival

proe

x(2

3)y

yy

yLe

sser

etal

.[6

1]P

aral

lel

Ora

lD

PN

Pla

cebo

(97)

Pre

gaba

lin(7

7)P

rega

balin

(82)

Pre

gaba

lin(8

2)y

yy

yLe

vend

oglu

etal

.[1

33]

Cro

ssov

erO

ral

Cen

tral

neur

opat

hic

pain

Pla

cebo

(20)

Gab

apen

tin(2

0)y

yy

n

Lync

het

al.

[53]

Par

alle

lTo

pica

lN

euro

path

icpa

inP

lace

bo(2

5)K

etam

ine

(22)

Am

itrip

tylin

e(2

2)A

mitr

ipty

line

+ke

tam

ine

(23)

yy

yy

Mai

eret

al.

[100

]P

aral

lel

Ora

lP

hant

omlim

bpa

inP

lace

bo(1

8)M

eman

tine

(18)

yy

yn

Man

icou

rtet

al.

[101

]P

aral

lel

Ora

lP

osttr

aum

atic

/po

stsu

rgic

alne

urop

athi

cpa

in

Pla

cebo

(20)

Ale

ndro

nate

(20)

yy

yn

Mar

iette

etal

.[1

34]

Par

alle

lIn

trav

enou

sD

PN

Pla

cebo

(12)

Alp

ha-in

terf

eron

(12)

yy

yy

McC

lean

e[8

4]P

aral

lel

Ora

lN

euro

path

icpa

inP

lace

bo(4

6)La

mot

rigin

e(4

6)y

yy

yM

cCle

ane

[82]

Par

alle

lTo

pica

lN

euro

path

icpa

inP

lace

bo(4

1)D

oxep

in(4

1)C

apsa

icin

(33)

Dox

epin

+ca

psai

cin

(36)

yy

yn

McC

lean

e[1

35]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Pla

cebo

(44)

L-36

5260

(44)

L-36

5260

(44)

yy

yn

Mei

eret

al.

[73]

Par

alle

lTo

pica

lN

euro

path

icpa

inP

lace

bo(3

0)Li

doca

ine

(28)

yy

yy

Mer

cada

nte

etal

.[1

36]

Cro

ssov

erO

ral

Can

cer

neur

opat

hic

pain

Pla

cebo

(16)

Am

itrip

tylin

e(1

6)y

yy

n

Mor

ley

etal

.[1

37]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Pla

cebo

(19)

Met

hado

ne(1

9)y

yy

yM

orle

yet

al.

[137

]C

ross

over

Ora

lN

euro

path

icpa

inP

lace

bo(1

7)M

etha

done

(17)

yy

yy

Nik

olaj

sen

etal

.[1

38]

Cro

ssov

erO

ral

Pha

ntom

limb

pain

Pla

cebo

(19)

Mem

antin

e(1

9)y

yy

n

Nik

olaj

sen

etal

.[1

02]

Par

alle

lO

ral

Pha

ntom

limb

pain

Pla

cebo

(23)

Gab

apen

tin(2

3)y

yy

y

Nor

rbrin

kan

dLu

ndeb

erg

[24]

Par

alle

lO

ral

Cen

tral

neur

opat

hic

pain

Pla

cebo

(12)

Tram

adol

(23)

yy

yy

Nur

mik

koet

al.

[31]

Par

alle

lO

ro-m

ucos

alN

euro

path

icpa

inP

lace

bo(6

2)S

ativ

ex(6

3)y

yy

yO

nofr

jeta

l.[9

1]P

aral

lel

Intr

amus

cula

rN

euro

path

icpa

inP

lace

bo(3

1)S

t200

(31)

St2

00(3

2)y

yy

nO

skar

sson

etal

.[8

9]P

aral

lel

Ora

lD

PN

Pla

cebo

(31)

Mex

iletin

e(3

1)M

exile

tine

(33)

Mex

iletin

e(3

1)y

yy

yO

ttoet

al.

[139

]C

ross

over

Ora

lD

PN

Pla

cebo

(37)

Val

proi

cac

id(3

7)y

yy

yO

ttoet

al.

[140

]C

ross

over

Ora

lD

PN

Pla

cebo

(47)

Esc

italo

pram

(47)

yy

yy

Raj

a[1

41]

Cro

ssov

erO

ral

PH

NP

lace

bo(7

6)M

orph

ine

(76)

Nor

trip

tylin

e(7

6)y

yy

yR

aoet

al.

[32]

Cro

ssov

erO

ral

Can

cer

neur

opat

hic

pain

Pla

cebo

(58)

Gab

apen

tin(5

7)y

yy

y

Rao

etal

.[2

8]P

aral

lel

Ora

lC

ance

rne

urop

athi

cpa

in

Pla

cebo

(62)

Lam

otrig

ine

(63)

yy

yy

Ras

kin

etal

.[6

4]P

aral

lel

Ora

lD

PN

Pla

cebo

(109

)To

pira

mat

e(2

14)

yy

yy

Ras

kin

etal

.[4

9]P

aral

lel

Ora

lD

PN

Pla

cebo

(116

)D

ulox

etin

e(1

16)

Dul

oxet

ine

(116

)y

yy

yR

auck

etal

.[3

9]P

aral

lel

Ora

lD

PN

Pla

cebo

(59)

Laco

sam

ide

(60)

yy

yy

Ric

ean

dM

aton

[96]

Par

alle

lO

ral

PH

NP

lace

bo(1

11)

Gab

apen

tin(1

15)

Gab

apen

tin(1

08)

yy

yy

Ric

hter

etal

.[5

9]P

aral

lel

Ora

lD

PN

Pla

cebo

(85)

Pre

gaba

lin(7

9)P

rega

balin

(82)

yy

yy

Rin

tala

etal

.[1

42]

Cro

ssov

erO

ral

Cen

tral

neur

opat

hic

pain

Act

ive

plac

ebo

(38)

Gab

apen

tin(3

8)A

mitr

ipty

line

(38)

yy

yy

Ros

enst

ock

etal

.[6

7]P

aral

lel

Ora

lD

PN

Pla

cebo

(70)

Pre

gaba

lin(7

6)y

yy

y

581


Dow


ic.oup.com/painm


Tab

le1

Con

tinue

d

Stu

dyD

esig

nR

oute

ofA

dmin

istr

atio

nC

ondi

tion

Trea

tmen

t1

(Sub

ject

sR

ando

miz

ed)

Trea

tmen

t2

(Sub

ject

sR

ando

miz

ed)

Trea

tmen

t3

(Sub

ject

sR

ando

miz

ed)

Trea

tmen

t4

(Sub

ject

sR

ando

miz

ed)

Dou

ble

Blin

dR

ando

miz

atio

nA

ppro

pria

teA

lloca

tion

Con

ceal

edD

escr

iptio

nof

Dro

pout

s

Ros

siet

al.

[23]

Par

alle

lO

ral

Cen

tral

neur

opat

hic

pain

Pla

cebo

(8)

Leve

tirac

etam

(12)

yy

yy

Row

both

amet

al.

[85]

Par

alle

lO

ral

PH

NP

lace

bo(1

16)

Gab

apen

tin(1

13)

yy

yy

Row

both

amet

al.

[66]

Par

alle

lO

ral

DP

NP

lace

bo(8

1)V

enla

faxi

ne(8

1)V

enla

faxi

ne(8

2)y

yy

yR

owbo

tham

etal

.[1

9]P

aral

lel

oral

DP

NP

lace

bo(6

2)Te

bani

clin

e(6

4)Te

bani

clin

e(6

7)Te

bani

clin

e(6

6)y

yy

yS

abat

owsk

ieta

l.[7

0]P

aral

lel

Ora

lP

HN

Pla

cebo

(81)

Pre

gaba

lin(8

1)P

rega

balin

(76)

yy

yy

Sal

imet

al.

[58]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Pla

cebo

(11)

Ver

um(1

0)y

yy

yS

chifi

ttoet

al.

[45]

Par

alle

lO

ral

HIV

-ass

ocia

ted

neur

opat

hic

pain

Pla

cebo

(21)

Mem

antin

e(2

4)un

know

nun

know

nun

know

nn

Sch

ley

etal

.[1

03]

Par

alle

lO

ral

Pha

ntom

limb

pain

Pla

cebo

(9)

Mem

antin

e(1

0)y

yy

n

Sch

war

tzm

anet

al.

[104

]P

aral

lel

Ora

lP

osttr

aum

atic

/po

stsu

rgic

alne

urop

athi

cpa

in

Pla

cebo

(10)

Ket

amin

e(9

)y

yy

n

Sel

vara

jah

etal

.[1

7]P

aral

lel

Oro

-muc

osal

DP

NP

lace

bo(1

5)S

ativ

ex(1

5)y

yy

yS

emen

chuk

etal

.[1

43]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Pla

cebo

(41)

Bup

ropi

onsr

(41)

yy

yy

Ser

pell

[79]

Par

alle

lO

ral

Neu

ropa

thic

pain

Pla

cebo

(152

)G

abap

entin

(153

)y

yy

yS

hack

elfo

rdet

al.

[22]

Par

alle

lO

ral

PH

NP

lace

bo(6

6)G

w40

6381

(72)

Gw

4063

81(7

1)y

yy

yS

haib

anie

tal.

[21]

Par

alle

lO

ral

DP

NP

lace

bo(6

5)La

cosa

mid

e(1

41)

Laco

sam

ide

(125

)La

cosa

mid

e(1

37)

yy

yy

Sid

dall

etal

.[4

2]P

aral

lel

Ora

lC

entr

alne

urop

athi

cpa

in

Pla

cebo

(67)

Pre

gaba

lin(7

0)y

yy

y

Silv

eret

al.

[34]

Par

alle

lO

ral

Neu

ropa

thic

pain

Pla

cebo

(109

)La

mot

rigin

e(1

11)

yy

yy

Sim

pson

etal

.[7

5]P

aral

lel

Ora

lH

IV-a

ssoc

iate

dne

urop

athi

cpa

in

Pla

cebo

(47)

Lam

otrig

ine

(88)

yy

yy

Sim

pson

etal

.[1

5]P

aral

lel

Ora

lH

IV-a

ssoc

iate

dne

urop

athi

cpa

in

Pla

cebo

(151

)P

rega

balin

(151

)y

yy

y

Sin

drup

etal

.[5

1]P

aral

lel

Ora

lD

PN

Pla

cebo

(42)

Tka

731

(44)

yy

yn

Sm

ithet

al.

[144

]C

ross

over

Ora

lP

hant

omlim

bpa

inP

lace

bo(2

4)G

abap

entin

(24)

yy

yn

Sta

cey

etal

.[9

3]P

aral

lel

Ora

lP

HN

Pla

cebo

(90)

Pre

gaba

lin(8

8)P

rega

balin

(91)

yy

yy

Sve

ndse

net

al.

[68]

Cro

ssov

erO

ral

Cen

tral

neur

opat

hic

pain

Pla

cebo

(12)

Dro

nabi

nol(

12)

yy

yn

Taie

tal.

[145

]C

ross

over

Ora

lC

entr

alne

urop

athi

cpa

in

Pla

cebo

(14)

Gab

apen

tin(1

4)y

yy

n

Tasm

uth

etal

.[1

46]

Cro

ssov

erO

ral

Can

cer

neur

opat

hic

pain

Pla

cebo

(15)

Ven

lafa

xine

(15)

Ven

lafa

xine

(15)

yy

yy

Thi

enel

etal

.[6

5]P

aral

lel

Ora

lD

PN

Pla

cebo

(136

)To

pira

mat

e(1

28)

Topi

ram

ate

(130

)To

pira

mat

e(1

30)

yy

yy

Thi

enel

etal

.[6

5]P

aral

lel

Ora

lD

PN

Pla

cebo

(119

)To

pira

mat

e(1

16)

Topi

ram

ate

(129

)y

yy

yT

hien

elet

al.

[65]

Par

alle

lO

ral

DP

NP

lace

bo(1

26)

Topi

ram

ate

(122

)To

pira

mat

e(1

23)

yy

yy

582

Cepeda et al.

Dow


ic.oup.com/painm


Tolle

etal

.[3

5]P

aral

lel

Ora

lD

PN

Pla

cebo

(96)

Pre

gaba

lin(9

9)P

rega

balin

(99)

Pre

gaba

lin(1

01)

yy

yy

van

deV

usse

etal

.[6

3]C

ross

over

Ora

lP

osttr

aum

atic

/po

stsu

rgic

alne

urop

athi

cpa

in

Pla

cebo

(29)

Gab

apen

tin(2

9)y

yy

y

van

Sev

ente

ret

al.

[48]

Par

alle

lO

ral

PH

NP

lace

bo(9

4)P

rega

balin

(87)

Pre

gaba

lin(9

8)P

rega

balin

(91)

yy

yy

van

Sev

ente

ret

al.

[14]

Par

alle

lO

ral

Pos

ttrau

mat

ic/

post

surg

ical

neur

opat

hic

pain

Pla

cebo

(127

)P

rega

balin

(127

)y

yy

y

Var

enna

etal

.[1

05]

Par

alle

lO

ral

Pos

ttrau

mat

ic/

post

surg

ical

neur

opat

hic

pain

Pla

cebo

(17)

Clo

dron

ate

(15)

yy

yy

Ves

terg

aard

etal

.[1

47]

Cro

ssov

erO

ral

Cen

tral

neur

opat

hic

pain

Pla

cebo

(30)

Am

itrip

tylin

e(3

0)y

yy

y

Vilh

olm

etal

.[1

08]

Cro

ssov

erO

ral

Pos

ttrau

mat

ic/

post

surg

ical

neur

opat

hic

pain

Pla

cebo

(27)

Leve

tirac

etam

(27)

yy

yy

Vin

iket

al.

[41]

Par

alle

lO

ral

DP

NP

lace

bo(9

0)La

mot

rigin

e(9

0)La

mot

rigin

e(9

0)La

mot

rigin

e(9

0)y

yy

yV

rank

enet

al.

[50]

Par

alle

lO

ral

Cen

tral

neur

opat

hic

pain

Pla

cebo

(11)

S(+

)-ke

tam

ine

(11)

S(+

)-ke

tam

ine

(11)

yy

yn

Vra

nken

etal

.[3

3]P

aral

lel

Ora

lC

entr

alne

urop

athi

cpa

in

Pla

cebo

(20)

Pre

gaba

lin(2

0)y

yy

y

Vre

them

etal

.[1

48]

Cro

ssov

erO

ral

DP

NP

lace

bo(1

9)A

mitr

ipty

line

(19)

Map

rotil

ine

(19)

yy

yy

Vre

them

etal

.[1

48]

Cro

ssov

erO

ral

DP

NP

lace

bo(1

8)A

mitr

ipty

line

(18)

Map

rotil

ine

(18)

yy

yy

Wal

lace

etal

.[1

49]

Cro

ssov

erO

ral

Neu

ropa

thic

pain

Pla

cebo

(20)

Mex

iletin

e(2

0)y

yy

nW

alla

ceet

al.

[77]

Par

alle

lO

ral

Neu

ropa

thic

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Pla

cebo

(31)

Gv1

9677

1(3

2)y

yy

yW

alla

ceet

al.

[72]

Cro

ssov

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ral

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ropa

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cebo

(41)

4030

w92

(41)

yy

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son

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ul[1

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ssov

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yy

yn

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son

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.[1

51]

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ssov

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ral

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NA

ctiv

epl

aceb

o(4

5)

Oxy

codo

ne(4

5)y

yy

y

Wer

nick

eet

al.

[43]

Par

alle

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ral

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bo(1

08)

Dul

oxet

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(114

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ulox

etin

e(1

12)

yy

yy

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er-S

mith

etal

.[1

52]

Par

alle

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ral

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ntom

limb

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cebo

(31)

Tram

adol

(33)

Am

itrip

tylin

e(3

0)y

yy

n

Win

deba

nket

al.

[153

]P

aral

lel

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lN

euro

path

icpa

inP

lace

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0)Ig

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yy

yn

Wrig

htet

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alle

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PN

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(93)

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ide

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lace

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entin

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yy

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ean

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sio

[36]

Par

alle

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-ass

ocia

ted

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opat

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cebo

(47)

L-ca

rniti

ne(4

3)y

yy

y

Yuc

elet

al.

[54]

Par

alle

lO

ral

Neu

ropa

thic

pain

Pla

cebo

(19)

Ven

lafa

xine

(19)

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lafa

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(17)

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al.

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ross

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cal

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Act

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gler

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6]P

aral

lel

Ora

lD

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Pla

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(74)

Laco

sam

ide

(150

)La

cosa

mid

e(1

33)

yy

yY

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The unadjusted responder rate in each neuropathic painsyndrome, along with the number of trials and number ofsubjects in each of the pain syndromes, can be found inTable 4.

After adjusting for potential confounders, trials thatassessed central pain and postherpetic neuralgia hadlower placebo responses than trials evaluating diabeticneuropathic/polyneuropathic pain. Similar to the painintensity analysis, a higher placebo response wasobserved for the trials that assessed HIV-related neuro-pathic pain compared with the trials evaluating diabeticneuropathic/polyneuropathic pain (Table 6).

These findings translate into a predicted placebo-inducedresponder rate using a random-effects model in subjectswith diabetic neuropathic/polyneuropathic pain of 20.2%(95% CI, 14.6 to 25.8), 7.2% (95% CI, 2.1 to 12.3) insubjects with central pain, 11.5% (95% CI, 8.4 to 14.5) insubjects with postherpetic neuralgia, and 42.8% (95% CI,34.9 to 50.7) in subjects with HIV-associated neuropathicpain (Figure 3). When the fixed-effects model was used,the predicted placebo-induced responder rate differedfrom the random-effects model predictions for diabeticneuropathic/polyneuropathic pain and phantom pain (itwas roughly half) due to the high levels of heterogeneity.

In terms of the effect of drug class on the placeboresponse, the trials that assessed NMDA blockers had asmaller placebo response than in trials in which anticon-vulsants were used 15.7% lower (1.0% to 30.4) (Table 6).

Age was positively associated with the placebo response(the higher the age, the greater the placebo response).With each increasing year in age, the placebo responseincreased 0.81% (95% CI, 0.01% to 1.6%). Note that thisfinding is adjusted for neuropathic pain syndrome and asa result, is not simply an artifact of an association betweenpain syndrome and mean age.

Mean baseline pain intensity and year of completion of thestudy did not affect the placebo responder rate response.

Table 2 Outcomes assessed in the included trials

Outcome

Numberof Trials(N = 141)

Numberof Subjects(N = 6,239)

Baseline pain intensity 131 6,205Posttreatment pain intensity 130 6,226Mean change from baseline in

pain intensity132 6,239

�30% reduction in pain intensityfrom baseline values

34 2,420


47 3,087


7 633

Tab

le3

Type

oftr

eatm

ents

asse

ssed

inth

eac

tive

arm

ofth

etr

ials

incl

uded

inth

ean

alys

isof

pain

inte

nsity

and/

orpa

inre

lief

byne

urop

athi

cpa

insy

ndro

me

Neu

ropa

thic

Pai

nS

yndr

ome,

N(%

)A

ntic

onvu

lsan

tsA

ntid

epre

ssan

tsC

anna

bino

ids

NM

DA

Rec

epto

rA

ntag

onis

tsO

pioi

ds

Sod

ium

Cha

nnel

Blo

cker

sC

ombi

natio

nN

ontr

aditi

onal

Tota

l

Can

cer

neur

opat

hic

pain

3(7

5)—

——

1(2

5)—

——

4(4

.0)

Cen

tral

neur

opat

hic

pain

4(5

7.1)

—1

(14.

3)1

(14.

3)1

(14.

3)—

——

7(6

.9)

Dia

betic

neur

opat

hic/

poly

neur

opat

hic

pain

23(5

7.5)

4(1

0.0)

1(2

.5)

1(2

.5)

3(7

.5)

2(5

.0)

1(2

.5)

5(1

2.5)

40(3

9.6)

HIV

-ass

ocia

ted

neur

opat

hic

pain

3(5

0)—

—1

(16.

7)—

1(1

6.7)

—1

(16.

7)6

(5.9

)

Neu

ropa

thic

pain

(uns

peci

fied)

4(2

6.7)

1(6

.7)

3(2

0.0)

1(6

.7)

—2

(13.

3)3

(20.

0)1

(6.7

)15

(14.

7)

Pha

ntom

pain

1(1

6.7)

——

3(5

0.0)

1(1

6.7)

—1

(16.

7)—

6(5

.8)

Pos

ther

petic

neur

algi

a8

(57.

1)1

(7.1

4)—

—1

(7.1

4)—

1(7

.14)

3(2

1.4)

14(1

3.9)

Pos

ttrau

mat

ic/p

osts

urgi

cal

pain

/CR

PS

4(4

4.4)

2(2

2.2)

1(1

1.1)

2(2

2.2)

9(8

.9)

Tota

l50

(49.

5)6

(5.9

4)5

(4.9

)9

(8.9

)7

(6.9

)6

(5.9

4)6

(5.9

4)12

(11.

9)10

1(1

00)

CR

PS

=co

mpl

exre

gion

alpa

insy

ndro

me;

HIV

=hu

man

imm

unod

efici

ency

viru

s;N

MD

A=

N-m

ethy

ld-a

spar

tate

.

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Discussion

This comprehensive, systematic search and meta-analysis showed substantial variation in placebo responsein the different types of pain syndromes evaluated. Themagnitude of the placebo-induced decline in pain intensityfrom baseline could be as large as 1.8 units with a 42.8%responder rate in subjects with HIV-associated neuro-pathic pain or as small as 0.5 units with a 7.2% responderrate in subjects with central neuropathic pain.

Postherpetic neuralgia and central pain were associatedwith smaller placebo responses, and HIV-associated painwas associated with a higher placebo response in bothpain intensity and responder rate analyses. This consis-tency across analyses provides confidence in our results.A previous study also supports the finding that posther-petic neuralgia has a smaller placebo response [9] thanpainful diabetic neuropathy, but the authors are not awareof studies that have evaluated the placebo response inother neuropathic pain syndromes.

Phantom pain was associated with a higher placeboresponse than diabetic neuropathic/polyneuropathic painin the pain intensity analysis, but not in the responder rateTa

ble

4U

nadj

uste

dpl

aceb

o-in

duce

dde

crea

sein

pain

inte

nsity

from

base

line

and

resp

onde

rra

teby

neur

opat

hic

pain

synd

rom

e

Neu

ropa

thic

Pai

nS

yndr

ome

Num

ber

ofTr

ials

inth

eP

ain

Inte

nsity

Ana

lysi

s

Num

ber

ofS

ubje

cts

inth

eP

ain

Inte

nsity

Ana

lysi

s

Mea

nB

asel

ine

Pai

nIn

tens

ity�

Sta

ndar

dD

evia

tion

Mea

nD

ecre

ase

inP

ain

Inte

nsity

from

Bas

elin

e(0

–10

Sca

le)

Num

ber

ofTr

ials

inth

eR

espo

nder

Ana

lysi

s

Num

ber

ofS

ubje

cts

inth

eR

espo

nder

Ana

lysi

s

Mea

nP

lace

boR

espo

nder

Rat

es(�

50%

Pai

nR

elie

f)

Can

cer

neur

opat

hic

pain

413

85.

5�

1.3

-1.5

1—

——

Cen

tral

neur

opat

hic

pain

612

86.

5�

1.4

-0.5

03

997.

1D

iabe

ticne

urop

athi

c/po

lyne

urop

athi

cpa

in39

2,96

96.

4�

1.5

-1.4

220

1,63

021

.1

HIV

-ass

ocia

ted

neur

opat

hic

pain

628

06.

0�

1.9

-1.6

01

150

43.0

Neu

ropa

thic

pain

(uns

peci

fied)

1363

76.

6�

1.6

-0.7

98

436

13.4

Pha

ntom

pain

457

6.0

�0.

9-2

.35

483

18.0

Pos

ther

petic

neur

algi

a14

839

6.3

�1.

5-1

.17

961

412

.2P

osttr

aum

atic

/pos

tsur

gica

lpa

in/C

RP

S8

269

5.6

�2.

0-0

.31

275

23.0

CR

PS

=co

mpl

exre

gion

alpa

insy

ndro

me;

HIV

=hu

man

imm

unod

efici

ency

viru

s.

Table 5 Adjusted placebo-induced meandecrease in pain intensity by type of neuropathicpain syndrome and pain treatment in the active arm

Mean Decreasein Pain Intensityfrom Baseline

95% CI

Lower Upper

Neuropathic pain syndromeDiabetic neuropathic/

polyneuropathic painReference — —

Cancer neuropathic pain 0.03 -0.87 0.92Central neuropathic pain 1.02* 0.18 1.86HIV-associated neuropathic pain -0.50* -0.77 -0.23Neuropathic pain (unspecified) 0.53 -0.06 1.13Phantom pain -1.80* -2.90 -0.69Postherpetic neuralgia 0.17* 0.008 0.33Posttraumatic/postsurgical

pain/CRPS0.66* 0.39 0.94

Treatment classAnticonvulsants Reference — —Antidepressants 0.002 -0.68 0.69Cannabinoids 0.36 -0.62 1.34NMDA receptor antagonists 0.87* 0.04 1.71Opioids -0.37 -1.07 0.33Sodium channel blockers 0.72 -0.30 1.73Combination 0.59 -0.33 1.51Nontraditional 0.33 -0.24 0.89

For example, the mean decrease in pain intensity from baseline in centralneuropathic pain was 1.02 units smaller than the trials that evaluated diabeticneuropathic/polyneuropathic pain. If the 95% CI includes “0,” the decline inpain intensity in a specific pain syndrome is not statistically significantlydifferent from the decline in diabetic neuropathic/polyneuropathic pain. Nega-tive numbers indicate a larger placebo response compared with diabeticneuropathic/polyneuropathic pain.* Statistically significant result.CI = confidence interval; CRPS = complex regional pain syndrome;HIV = human immunodeficiency virus; NMDA = N-methyl d-aspartate.

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analysis. Similarly, posttraumatic/postsurgical pain/CRPSwas associated with a smaller placebo response thandiabetic neuropathic/polyneuropathic pain in the painintensity analysis, but not in the responder rate analysis.There was substantial heterogeneity in the responder rateanalysis despite the fact that we controlled for treatment inthe active arm, age, baseline pain intensity, and year ofpublication of the study. Therefore, caution is neededwhen interpreting the impact of these pain syndromes onthe placebo response. Interestingly, it has been found thatthe placebo response is higher when continuous out-comes are evaluated than when binary outcome areevaluated [111].

Placebo response rates can be large and clinicallyimportant [112,113] and dependent on the underlyingpain condition, which may help explain the quite sub-stantial failure rates sometimes observed in clinical trials.With such potentially large placebo responses for sub-jects with certain neuropathic pain conditions, the medi-cation under evaluation in the active arm must have avery large treatment effect in order to be able to differ-entiate from placebo. It has previously been observedthat the difference for currently available, proven effective

treatments from placebo ranges from 0.9 to 1.5 units[114], and results from the current study suggest theplacebo response could be as large as 1.8 units. There-fore, the findings of this study suggest that initial evalu-ation of new drugs should start in neuropathic painsyndromes with a lower placebo response, such ascentral pain or postherpetic neuralgia, to avoid inconclu-sive or false negative study results, which might lead tothe abandonment of the development of potentially effi-cacious new drugs.

The findings of the present study seem to indicate that theplacebo response might be also influenced by the type ofmedications under evaluation. This finding is not surprisingas subjects’ expectation of pain relief is a known factor forplacebo response. The reason the expectation of painrelief is lower with NMDA receptor antagonists than withanticonvulsants is not clear. Although many hypotheticalreasons could be generated, caution in over-interpretingthe results is warranted because the data in which theanalyses were conducted were sparse (i.e., not all of thedrugs were evaluated in all pain syndromes) and in thesecircumstances, the findings could be an artifact (i.e., afalse positive result) [115].

Cancer-associated neuropathic pain

Cancer-associated neuropathic pain

Central neuropathic pain


Diabetic neuropathic/polyneuropathic pain


HIV-associated neuropathic pain


Phantom pain

Phantom pain

Postherpetic neuralgia


Posttraumatic/postsurgical pain/CRPS


Syndrome

Random

Fixed

Random

Fixed

Random

Fixed

Random

Fixed

Random

Fixed

Random

Fixed

Random

Fixed

Model

-1.38 (-1.86, -0.90)

-1.33 (-1.65, -1.01)

-0.53 (-0.86, -0.19)

-0.53 (-0.86, -0.19)

-1.45 (-1.55, -1.35)

-1.46 (-1.53, -1.40)

-1.82 (-2.12, -1.51)

-1.91 (-2.13, -1.68)

-2.61 (-3.55, -1.68)

-2.69 (-3.18, -2.19)

-1.16 (-1.29, -1.03)

-1.16 (-1.29, -1.03)

-0.46 (-0.80, -0.12)

-0.62 (-0.85, -0.39)

intensity (95% CI)

Mean pain

52.1

0

49.7

27.6

70.3

0

41.2

squared

I

-1.38 (-1.86, -0.90)

-1.33 (-1.65, -1.01)

-0.53 (-0.86, -0.19)

-0.53 (-0.86, -0.19)

-1.45 (-1.55, -1.35)

-1.46 (-1.53, -1.40)

-1.82 (-2.12, -1.51)

-1.91 (-2.13, -1.68)

-2.61 (-3.55, -1.68)

-2.69 (-3.18, -2.19)

-1.16 (-1.29, -1.03)

-1.16 (-1.29, -1.03)

-0.46 (-0.80, -0.12)

-0.62 (-0.85, -0.39)

intensity (95% CI)

Mean pain

52.1

0

49.7

27.6

70.3

0

41.2

squared

I

enilesabmorfdesaercedniaP

0-3 -2 -1 0

Figure 2 Forest plot with the predicted placebo-induced mean decrease in pain intensity using the fixed andrandom-effects models by neuropathic pain syndrome.

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Phantom pain

Phantom pain





Syndrome

Random

Fixed

Random

Fixed

Random

Fixed

Random

Fixed

Random

Fixed

Random

Fixed

Model

0.07 (0.02, 0.12)

0.07 (0.02, 0.12)

0.20 (0.15, 0.26)

0.13 (0.11, 0.14)

0.43 (0.35, 0.51)

0.43 (0.35, 0.51)

0.15 (-0.01, 0.30)

0.07 (0.02, 0.12)

0.12 (0.08, 0.14)

0.11 (0.09, 0.14)

0.20 (0.07, 0.32)

0.18 (0.09, 0.26)

50% relief (95% CI)

subjects with >=

Proportion of

0

91.6

81.6

28.5

42.9

squared

I

0.07 (0.02, 0.12)

0.07 (0.02, 0.12)

0.20 (0.15, 0.26)

0.13 (0.11, 0.14)

0.43 (0.35, 0.51)

0.43 (0.35, 0.51)

0.15 (-0.01, 0.30)

0.07 (0.02, 0.12)

0.12 (0.08, 0.14)

0.11 (0.09, 0.14)

0.20 (0.07, 0.32)

0.18 (0.09, 0.26)

50% relief (95% CI)

subjects with >=

Proportion of

0

91.6

81.6

28.5

42.9

squared

I

feilerhtiwstcejbusfonoitroporP

00 .1 .2 .3 .4

Figure 3 Forest plot with the predicted placebo-induced �50% pain relief using the fixed and random-effects models by neuropathic pain syndrome.

Table 6 Adjusted responder rate by type of neuropathic pain syndrome and pain treatment in the activearm

ResponderRate

95% CI

Lower Upper

Neuropathic pain syndromeDiabetic neuropathic/polyneuropathic pain Reference — —Central neuropathic pain -0.12* -0.22 -0.01HIV-associated neuropathic pain 0.31* 0.06 0.57Neuropathic pain (unspecified) -0.13 -0.12 0.10Phantom pain 0.06 -0.10 0.22Postherpetic neuralgia -0.14* -0.26 -0.25Posttraumatic/postsurgical pain/CRPS 0.02 -0.17 0.21

Treatment classAnticonvulsants Reference — —Antidepressants 0.05 -0.07 0.18Cannabinoids -0.09 -0.23 0.05NMDA receptor antagonists -0.15* -0.30 -0.01Opioids -0.02 -0.19 0.15Combination -0.05 -0.22 0.11Nontraditional -0.079 -0.22 0.06

If the 95% CI includes “0,” the responder rate in a specific pain syndrome is not statistically significantly different from the responder rate indiabetic neuropathic/polyneuropathic pain. Negative numbers indicate a lower placebo response compared with diabetic neuropathic/polyneuropathic pain.* Statistically significant result.CI = confidence interval; CRPS = complex regional pain syndrome; HIV = human immunodeficiency virus; NMDA = N-methyl d-aspartate.

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Findings of this study also indicated that higher age wasassociated with higher responder rates, but was notassociated with a decline in pain intensity. The number oftrials that reported responder rates was much lower thanthe number of trials that reported pain intensity; as aresult, the findings could be the consequence of analyzingonly a subset of studies. In the literature, the association ofage with placebo response ranges from no effect[116,117] to increasing age being associated withdecreasing the placebo response (i.e., opposite to thefinding in this current study) [118].

Although the current analyses were controlled for theeffect of study design characteristics and subject charac-teristics that could be associated with placebo response,no adjustments were made for use of rescue medicationsin the trial. In order for this or other unmeasured variablesto invalidate the results, the effect of these variables on theplacebo response has to be differential in the pain syn-dromes, which seems unlikely.

In this study, the placebo response for achieving aresponder rate of at least 50% pain relief was assessed;however, an unanswered question is whether the placeboresponse changes depending on the selection of thecutoff value used to define a “responder” (e.g., at least30% pain relief, total pain relief). This question could beaddressed by selecting and analyzing trials that reportmultiple responder rates.

Placebo response is substantial in neuropathic pain.Understanding the placebo response could lead toimprovements in study design that will enhance the likeli-hood of detecting beneficial treatments and avoid theabandonment of medications due to erroneous percep-tions of lack of efficacy. When designing clinical trials toassess the efficacy of drugs, the pain syndrome should beconsidered.

Acknowledgment

This study was funded by Janssen Global Services, LLC.

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154 Wymer JP, Simpson J, Sen D, Bongardt S. Efficacyand safety of lacosamide in diabetic neuropathicpain: An 18-week double-blind placebo-controlledtrial of fixed-dose regimens. Clin J Pain2009;25:376–85.

155 Yelland MJ, Poulos CJ, Pillans PI, et al. N-of-1 ran-domized trials to assess the efficacy of gabapentinfor chronic neuropathic pain. Pain Med2009;10:754–61.

156 Yuen KC, Baker NR, Rayman G. Treatment ofchronic painful diabetic neuropathy with isosorbidedinitrate spray: A double-blind placebo-controlledcross-over study. Diabetes Care 2002;25:1699–703.

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Appendix 1

Search Criteria Search Hits

1 Title = carpal tunnel syndrome (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND carpal tunnelsyndrome[Title]

20Type = RCTAny Field = placeboLanguage = English

2 Title = phantom (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND phantom[Title]

11Type = RCTAny field = placeboLanguage = English

3 Title = postamputation (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) ANDpostamputation[Title]


4 Title = central pain (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND central pain[Title]


5 Title = complex regional pain (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND complex regionalpain[Title]


6 Title = trigeminal (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND trigeminal[Title]


9 Title = reflex sympathetic dystrophy (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND reflex sympatheticdystrophy[Title]


10 Title = polyneuropathy (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) ANDpolyneuropathy[Title]


11 Title = postmastectomy (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) ANDpostmastectomy[Title]


12 Title = postthoracotomy (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) ANDpostthoracotomy[Title]


15 Any field = neuropath* (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND neuropath*[Title]

594Any field = placeboType = RCTLanguage = English

16 Any field = neuralg* (((English[Language]) AND randomized controlledtrial[Publication Type]) AND placebo) AND neuralg*[Title]

186Any field = placeboType = RCTLanguage = English

Total 782

Published in 1995 to Nov 2009and no duplicates

Total 624

595


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