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Text Summary: The Working Group reviewed all the primary studies extracted below.

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Supplementary File 1. Quality Assessment of Neuropathic Pain Treatment Options

Author(s)Quality of Evidence

Reasons for Downgrade

Reasons for Upgrade

Study Outcome

Type of Pain

Comparison Population Additional Comments

Is acupuncture effective in decreasing pain intensity in individuals with SCI?

Nayak

20011

Moderate Moderate

effect size

+ for overall

pain,

- for below-

level NP as

per SCIRE

NP

MS

None Total=31

SCI=21

NP=24

MS=7

Observational pre-post.

Norrbrink

20112

Moderate Small CI

ITT analysis

conducted

+ NP Massage Total=30

SCI=30

NP=30

Prospective observational controlled exploratory trial.

Is acupuncture more effective in decreasing pain intensity than massage therapy in individuals with SCI?

Norrbrink

20112

Moderate Small CI

ITT analysis

conducted

- NP Massage Total=30

SCI=30

NP=30

Prospective observational controlled trial.

Is electro-acupuncture effective in decreasing pain intensity in individuals with SCI?

Rapson

20033

Low + NP None Total=36

SCI=22

Postsurgical=2

MS=2

Guillain Barre=1

Transverse

myelitis=1

Cervical

myelitis=1

Observational case series: more effective for bilateral than

unilateral.



Reasons for Upgrade

Study Outcome

Type of Pain


Syringomyelia=1

Other=6

Is alfentanil effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Eide 19954 Moderate Small

sample size

+ NP (1) Ketamine

(2) Placebo

Total=9

SCI=9

NP=9

RCT. Alfentanil effective vs placebo, but no significant

difference vs ketamine.

Is amitriptyline more effective than placebo in reducing neuropathic pain intensity for persons with spinal cord injury?

Rintala

20075

High + NP (1) Gabapentin-

amitriptyline-

diphenhydramine

(2) GDA (3) AGD

(4) ADG (5) DGA

(6) DAG

Total=22

SCI=22

NP=22

RCT. Between groups (week 8): average pain intensity in all

subjects significantly lower for amitriptyline. Amitriptyline

significantly more effective than diphenhydramine.

Cardenas

20026

High - NP

MS

Placebo:

Benzotropine

mesylate

Total=84

SCI=84

NP=51

MS=33

RCT. Between groups: no difference between placebo and

active treatment for central pain.

Is amitriptyline more effective than gabapentin in reducing neuropathic pain intensity for persons with spinal cord injury?

Rintala

20077

High + NP (1) Gabapentin-

amitriptyline-

diphenhydramine

(2) GDA (3) AGD

(4) ADG (5) DGA

(6) DAG

Total=22

SCI=22

NP=22

RCT. Between groups: amitriptyline more effective at week 8 in

reducing pain intensity than gabapentin (t 2.32, p .03; effect

size, Cohen d .55)

Are cannabinoids effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Rintala

20108

Low Small

sample size

(N=5). Wide

- NP Active placebo

(diphenhydramine)

Total=7

SCI=7

NP=7

RCT. Between groups: pain intensity not significantly different

between dronabinol and diphenhydramine groups.



Reasons for Upgrade

Study Outcome

Type of Pain


CIs

Is cognitive behavioural therapy effective in decreasing pain intensity in individuals with SCI?

Perry 20109 Moderate Medium CIs

Provided p

values.

- pain intensity NP

MS

Standard treatment Total=36

SCI=36

NP=32

MS=3

Other=1

Prospective observational controlled trial.

Norrbrink

Budh

200610

Moderate CIs and NNT

provided. Two

groups.

- NP Standard treatment N=38

SCI=38

NP=38

Prospective observational controlled trial. Pain intensity

unchanged, although mood, sleep, improved

Heutink

201211

High - NP Wait list control N=61

SCI=61

NP=61

RCT: (1) Pain intensity decreased over time (p <.01); no

intervention-related effects seen. (2) SS difference in pain

intensity between groups post-intervention, but not at 3-month

follow-up.

Burns

201312

Low - NP

MS

None (pre/post) Total=17

SCI=17

NP16

MSK=1

Prospective observational cohort: no SS improvement in pain

severity subscale of MPI post-intervention or at 12 months.

Is intrathecal combined clonidine and morphine more effective than placebo in reducing neuropathic pain intensity for persons with spinal cord injury?

Siddall

200013

Moderate Patient

assignment

not

discussed

+ NP Placebo (saline) Total=15

SCI=15

NP=15

RCT: Between groups: morphine + clonidine SS pain reduction

vs placebo.

Is intrathecal clonidine more effective than placebo in reducing neuropathic pain intensity for persons with spinal cord injury?

Siddall

200013

Moderate Patient

assignment

not

discussed

- NP Placebo (saline) Total=15

SCI=15

NP=15

RCT. Within groups: morphine or clonidine reduced mean pain

levels; not SS vs placebo.

Is DREZ effective in reducing neuropathic pain intensity for persons with spinal cord injury?



Reasons for Upgrade

Study Outcome

Type of Pain


Chun

201114

Low + NP Sindou's technique

vs modified MDT

Total=38

SCI=38

NP=38

Observational (pre-post).

Falci

200215

Moderate No incomplete

data or

selective

reporting.

Good

heterogeneity

of results.

Large effect

size.

+ NP Guide evoked vs

guide spontaneous

Total=41

SCI=41

NP=41

Prospective observational controlled trial: more effective in

below-level pain.

Spaic

200216

Low + NP 3 groups divided

based on subjective

sensory equivalents

Total=26

SCI=26

NP=26

Observational (case series)

Sindou

200117

Low + NP Total=44

SCI=40

Cauda equina=4

NP=44

Observational (case series)

Is duloxetine effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Vranken

201118

Moderate Wide CIs + NP Flexible-dose

placebo

Total=24

SCI=16

Stroke=8

NP=24

RCT. Within group: 2-point VAS reduction in pain intensity with

duloxetine at 8 weeks. Between groups: decrease in pain with

duloxetine vs control (p=.05), trend to significance. Between

groups: SS decrease in evoked pain score by brush (p=.019)

and by acetone (p<.001) with duloxetine vs placebo

Is exercise effective in decreasing pain intensity in individuals with SCI?

Ginis

200319

Low RCT Canada NP

MS

No exercise N=34

SCI=34

NP=Not stated

Changes in potential mediators at 3 months; SS decrease with

treatment vs control (p=.03). After controlling for baseline pain

and stress, 3-month pain scores (r2=.15, p<.01)



Reasons for Upgrade

Study Outcome

Type of Pain


MS=Not stated

Ditor 200320 Low Pre-post

(follow-up)

Canada NP

MS

None N=7

SCI=7

NP=Not stated

MS=Not stated

Trend for increased pain (p=.07)

Is gabapentin effective in decreasing pain intensity in individuals with SCI?

Rintala

200720

High - NP Active placebo

(diphenhydramine)

Total=22

SCI=22

NP=22

RCT. Between groups: at week 8 no significant difference

between gabapentin and diphenhydramine.

Levendoglu

200421

High + NP Placebo Total=22

SCI=22

NP=22

RCT. Within groups: pain intensity decreased significantly for

gabapentin (p<.001). Between groups: pain intensity differed

between groups at all time periods (p<.001). VAS scores

indicated significant pain relief, beginning at week 2 and until

week 6 (p<.05). Pain relief between groups at end of stable

dosing periods significantly different (p<.000).

Tai 200222 Moderate Small

sample size

(N = 7)

- NP Placebo. Total=7

SCI=7

Neuropathic=7

RCT. Between groups: trends of reductions with gabapentin vs.

placebo for pain intensity (p=.094)

To 200223 Low + NP No comparison.

(standard treatment

gabapentin)

Total=44

SCI=44

NP=44

Observational case series: 76% reported reduction in NP. VAS

decreased from 8.86 pre-treatment to 4.13 post-treatment (6

months later) (p<.001).

Ahn 200324 Low + NP Both groups received

gabapentin : groups

differed by duration

of pain experienced

Total=31

SCI=26

Cauda equina=5

NP=31

Observational pre-post. Between groups: both groups had

lower mean scores (p<.05). Mean pain score for Group 1

decreased more than for Group 2 (p<.05).

Putzke

200225

Very Low + NP No comparison

(survey)

Total=21

SCI=21

NP=21

Observational case series: 67% of patients reported favourable

response to gabapentin



Reasons for Upgrade

Study Outcome

Type of Pain


Is hypnotic suggestion effective in decreasing pain intensity in individuals with SCI?

Jensen

200026

Low + NP

MS

Total=22

SCI=22


Is hypnotic suggestion more effective than biofeedback in decreasing pain intensity in individuals with SCI?

Jensen

200927

Moderate SD, not CI,

provided

+ NP Biofeedback Total=37

SCI=37

NP=37

RCT.

Is ketamine effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Kvarnstrom

200428

Moderate No power

calculation.

Protocol

unclear

(recruited/

excluded)

+ NP (1) Saline

(2) Lidocaine

Total=10

SCI=10

NP=10

RCT. Between groups: VAS scores significantly reduced for

ketamine vs placebo (p<.01)

Eide 19954 Moderate Small

sample size

(N = 9).

+ NP (1) Alfentanil

(2) Placebo

Total=9

SCI=9

NP=9

RCT. Between groups: ketamine significant (p<.04). Within

group: High correlation between ketamine concentration and

reduction of continuous pain (r=.78, p<.002); reduction of wind-

up-like pain (r=.83, p<.002) noted.

Is lamotrigine effective in decreasing pain intensity in individuals with SCI?

Finnerup

200229

Moderate Wide CIs - : No SS in

total sample

+: Incomplete

SCI

NP Placebo Total=30

SCI=30

NP=30

RCT. Between groups: no SS effect of lamotrigine in total

sample. Within group: Incomplete SCI: lamotrigine significantly

reduced pain at- or below-SCI level.

Is levetiracetam effective in decreasing pain intensity in individuals with SCI?

Finnerup

200930

High - NP Placebo Total=36

SCI=36

NP=36

RCT. No SS improvement in median pain intensity vs placebo

(p=.46).

Is lidocaine effective in reducing neuropathic pain intensity for persons with spinal cord injury?



Reasons for Upgrade

Study Outcome

Type of Pain


Finnerup

200531


SCI=24

NP=24

RCT. Between groups: lidocaine reduced pain vs placebo (total

group) (p<.01). Lidocaine superior to placebo at reducing pain

in those with (p<.01) and without (p<.048) evoked pain. More

patients reported pain relief with at- and below-level pain while

receiving lidocaine vs placebo.

Kvarnstrom

200428

Moderate No power

calculation.

Protocol

unclear

(recruited/

excluded)

- NP Placebo Total=10

SCI=10

NP=10

RCT. Between groups: No SS difference for lidocaine vs

placebo group (p=.60).

Attal 200032 Moderate Randomiza-

tion not

explained.

Large CIs

+ NP Placebo Total=16

SCI=10

Stroke=6

NP=16

RCT. Between groups: Lidocaine had greater effect than

placebo on pain from end of injection for up to 45 minutes post

injection (p<.05). More people received pain relief with lidocaine

than with placebo; however, relief waned by 60 minutes post

injection.

Is IV morphine more effective than placebo in reducing neuropathic pain intensity for persons with spinal cord injury?

Attal 200233 Low Small

sample size.

No power

calculation.

- (no SS

difference)

+ (reduction

in mechanical

allodynia with

morphine)

NP Placebo Total=15

SCI=9

Stroke=6

NP=15

RCT. Between groups: No SS difference between morphine

and placebo post injection. Those with pain relief from

morphine had greater relief (3x) than with placebo from 15 to 60

minutes post injection. Morphine produced reduction in intensity

of mechanical allodynia: SS reduction in dynamic mechanical

allodynia (p<.01) for up to 2 hours but not in other pains.

Is osteopathy more effective than pregabalin in decreasing pain intensity in individuals with SCI?

Arienti

201134

Low No

randomiza-

tion

description,

no blinding,

- NP Pregabalin Total=26

SCI=26

NP=26

RCT. Both groups showed similar rates of improvement.



Reasons for Upgrade

Study Outcome

Type of Pain


no CIs

Is combined osteopathy and pregabalin more effective either alone in decreasing pain intensity in individuals with SCI?

Arienti

201134

Low No power

analysis.

Significant

risk of bias.

+ (combined)

- (alone)

NP Pregabalin vs

pregabalin +

osteopathy vs

osteopathy

Total=26

SCI=26

NP=26

RCT. Between groups: highest pain relief with combined

therapy vs pregabalin (p=.05) and osteopathy (p=.001). No

difference in treatment with pregabalin vs osteopathy (p value

not reported).

Is oxycodone effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Barrera-

Chacon

201135

Moderate CIs provided.

NP sample.

+ NP No comparison.

Standard treatment

provided

Total=57

SCI=57

NP=57

Observational pre-post: pain intensity significantly decreased

after 3 months of oxycodone treatment (p<.001).

Is pregabalin effective in decreasing pain intensity compared to placebo in individuals with SCI?

Siddall

200636


SCI=137

NP=137"

RCT. Between groups: mean endpoint pain score lower in

pregabalin group (4.62) than placebo group (6.27; p <.001).

Vranken

200718

Moderate Wide CIs for

NNT

+ NP Placebo Total=40

SCI=21

Stroke=19

NP=40

RCT. Between groups: decrease in pain (p<.01) in treatment

group vs. control group.

Cardenas

201337


SCI=219

NP=219

RCT. Between groups: 150–600 mg/d effective in reducing

DAAC in pain over 16-week period [industry funding].

Is spinal cord stimulation effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Cioni

199538

Low - NP None Total=25

SCI=25

NP=25

40% had improvement

Is low transcutaneous electrical nerve stimulation (TENS) more effective than high TENS in decreasing pain intensity in persons with SCI?

Norrbrink

200939

Low - NP High intensity Total=24

SCI=24

Prospective observational controlled trial



Reasons for Upgrade

Study Outcome

Type of Pain


NP=24

Davis

197540

Very low Bias. No CIs

or

methodology

description.

- NP None Total=31

SCI=31

NP=31

Observational case series.

Is tramadol effective in reducing neuropathic pain intensity compared to placebo for persons with spinal cord injury?

Norrbrink

200941

Moderate Wide CIs + NP Placebo Total=35

SCI=35

NP=35

RCT. Between groups: significant difference in pain ratings

(p<.05).

Is transcranial electrical stimulation effective in decreasing pain intensity in individuals with SCI?

Tan 200642 Moderate RCT - NP

MS

Random assignment

to active or sham

CES. tCES or sham

tCES for 1hour for 21

days. Then sham

group offered

opportunity to

participate in open-

label tCES study.

Total=38

SCI=38

NP=23

MS=15

No significant difference between tCES and sham groups for

BPI. Average daily pain intensity For active tCES decreased

significantly (p=0.03) from pre- to post-assessment vs sham

tCES. Significant reduction in daily pain intensity for active

tCES (pre-post) (p=.02) but not sham tCES (p=.34). Open-label

trial: reduction in pain after tCES (p=.003).

Capel

200343

Moderate RCT + NP

MS

SCI subjects

randomly assigned to

tCES or sham BID x

4 days. After 8-week

washout, treatments

reversed for sham

tCES only. During

second half, all

received active

tCES. 3 subjects left

Total=30

SCI=20

NP=not stated

MS=not stated

Phase I: tCES group reported less severe pain vs baseline

(p=.0016); controls reported no change. Phase II: control group

(now receiving tCES) reported significantly less pain (p<.005).



Reasons for Upgrade

Study Outcome

Type of Pain


study early, 2 due to

interactions between

tCES and

medication.

Kumru

201344

Low Cohort + NP

MS

Cohorts:

(1) (N=18)=SCI + NP

(2) (N=20)=SCI +

non-NP

(3) (N=14)=healthy

matched

Daily transcranial

direct current

stimulation + visual

illusion therapy x 2

weeks. Visual

illusion: seated

participant viewed

video of matching

gender walking on

treadmill.

Total=52

SCI=38

Healthy non-

SCI=14

NP=18

Other pain=20

No pain=14

1. SCI + NP: 37.4% decrease in pain intensity post treatment.

2. 13 of 18 individuals with NP had 50% decrease in pain

intensity post treatment.

3. Evoked pain perception significantly lower in NP group vs

SCI non-NP and healthy controls.

4. Pain threshold significantly higher in NP group vs other two

groups.

Is transcranial direct current stimulation effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Fregni

200645

High + NP Sham Total=17

Active tDCS=11

Sham tDCS=6

Double-blinded RCT: significant main group effects of tDCS

after third treatment until end of treatment. Effects not

maintained at follow up.

Soler

201046

High -: Overall pain

+: Continuous

pain,

paroxysmal

pain even at

NP Sham and sham with

visual illusion

Total=40

SCI=40

NP=40

Double-blinded RCT



Reasons for Upgrade

Study Outcome

Type of Pain


2nd follow up

Wrigley

201347

High - NP Sham N=10 Double-blinded crossover RCT

Yoon

201448

Moderate Small CIs.

ITT analysis

conducted.

+ NP Sham N=16 Prospective controlled trial.

Ngernyam

201449

High + NP Sham N=20 Double-blinded crossover RCT: only 1 treatment provided.

Significant improvement of pain intensity in treatment group vs.

sham (based on results from 1 treatment).

Is transcranial magnetic stimulation effective in decreasing pain intensity in individuals with SCI?

Defrin

200750

Moderate Small

sample size

(N = 6)

- NP Sham Total=11

SCI=11

NP=11

RCT

Kang

200951

Moderate Small

sample size

- NP Sham Total=11

SCI=11

NP=11

RCT

Jette 201352 Moderate Wide CIs + NP Sham Total=16

SCI=16

NP=16

RCT

Is trazodone effective in reducing neuropathic pain intensity for persons with spinal cord injury?

Davidoff

198753

Low Randomiza-

tion not

explained.

ITT not used

for main

outcomes.

Risk of bias.

- NP Placebo Total=19

SCI=19

NP=19

RCT. Between groups: No SS differences.

Is valproate effective in decreasing pain intensity in individuals with SCI?

Drewes Low Incomplete - NP Placebo Total=20 RCT. Between groups: differences not SS.



Reasons for Upgrade

Study Outcome

Type of Pain


199454 reporting. No

dispersion.

No power

calculation.

PP analysis.

No

explanation

of

randomiza-

tion.

SCI=20

NP=20

Is visual imagery walking effective in decreasing pain intensity in individuals with SCI?

Soler

201055

High + (last day of

treatment)

- at follow-up

NP Control illusion Total=40

SCI=40

NP=40

RCT: SS effect on overall pain intensity with visual illusion last

day of treatment (6.4). SS effect on continuous pain last day of

treatment (4.9). SS effect on dysesthesia last day of treatment

and second follow-up (4.4).

Moseley

200756

Very low + NP Control illusion Total=5

SCI=5

NP=5

Observational pre-post: small sample size.

Gustin

200857

Low - NP Control illusion Total=15

SCI=15

NP=15


BPI: Brief pain inventory

CI: Confidence interval

DAAC: Duration-adjusted average change

ITT: Intention to treat

MDT: Microsurgical-DREZ-otomy

MPI: Multidimensional pain inventory

MS: Musculoskeletal

NNT: Number needed to treat

NP: Neuropathic pain

RCT: Randomized controlled trial

SCI: Spinal cord injury

SS: Statistical significance

tCES: Transcranial electrical stimulation

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2. Norrbrink C, Lundeberg T. Acupuncture and massage therapy for neuropathic pain following spinal cord injury: an exploratory study. Acupunct Med 2011;29(2):108–15.

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