Scolaris Content Display Scolaris Content Display

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 1

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 memantine vs. placebo, Outcome 1 change in pain intensity.
Figures and Tables -
Analysis 1.1

Comparison 1 memantine vs. placebo, Outcome 1 change in pain intensity.

Comparison 2 gabapentin vs. placebo, Outcome 1 change in pain intensity.
Figures and Tables -
Analysis 2.1

Comparison 2 gabapentin vs. placebo, Outcome 1 change in pain intensity.

Table 3. Jadad 1996 Criteria

Author, Year

1a.

1b.

 

1c.

2a.

 

2b.

2c.

3.

 

Total Score

Abraham 2003

0

0

0

1

1

0

1

3 / 5

Bone 2002

1

1

0

1

1

0

1

5 / 5

Casale 2009

1

1

0

1

1

0

0

4 / 5

Eichenberger 2008

1

1

0

1

1

0

1

5 / 5

Huse 2001

1

0

0

1

1

0

1

4 / 5

Jaeger 1992

1

0

0

1

0

0

1

3 / 5

Maier 2003

1

1

0

1

1

0

1

5 / 5

Nikolajsen 1996

1

0

0

1

1

0

0

3 / 5

Robinson 2004

1

1

0

1

1

0

1

5 / 5

Schwenkreis 2003

1

1

0

1

1

0

1

5 / 5

Smith 2005

1

1

0

1

1

0

0

4 / 5

Wieck 2004

1

0

0

1

1

0

0

3 / 5

Wu 2002

1

1

0

1

1

0

1

5 / 5

Figures and Tables -
Table 3. Jadad 1996 Criteria
Table 4. Van Tulder 2003 Criteria

Author, Year

A

B

C

D

E

F

G

H

I

J

K

Total Score

Abraham 2003

0

1

1

1

1

0

0

0

1

1

1

7 / 11

Bone 2002

1

1

1

1

1

0

0

1

1

1

1

9 / 11

Casale 2009

1

1

1

1

1

1

0

1

1

1

1

10 / 11

Eichenberger 2008

1

1

1

1

1

0

0

1

1

1

1

9 / 11

Huse 2001

0

1

1

1

1

0

1

0

1

1

1

8 / 11

Jaeger 1992

0

0

1

1

0

0

0

1

1

1

1

6 / 11

Maier 2003

1

1

1

1

1

0

0

1

1

1

1

9 / 11

Nikolajsen 1996

0

1

1

1

1

0

0

1

1

1

1

8 / 11

Robinson 2004

1

1

1

1

1

1

1

0

1

1

0

9 / 11

Schwenkreis 2003

1

1

1

1

1

1

0

1

1

1

0

9 / 11

Smith 2005

1

1

1

1

1

1

0

0

0

1

0

7 / 11

Wieck 2004

1

1

1

1

1

0

0

0

1

1

1

8 / 11

Wu 2002

1

1

1

1

1

0

1

1

1

1

0

9 / 11

Figures and Tables -
Table 4. Van Tulder 2003 Criteria
Table 1. Summary of Characteristics of Included Studies

Author, yr

Number of patients

Characteristics of population

Methodology

Follow‐up

Drop‐outs/ withdrawals

Quality score

 

 

 

 

 

 

 

Jadad

Van Tulder

NMDA antagonists

 

 

 

 

 

 

 

Memantine

 

 

 

 

 

 

 

Maier 2003

36

 

29 males, median age 62 yrs; majority traumatic upper and lower limb amputation; at least 12 mos PLP history;  at least 4 on 11pt NAS

Randomised, DB, parallel; CGR

 

End of 3 wks

 

Two in treatment group due to side affects; three in placebo due to insufficient analgesia

5

9

Wieck 2004

 

8

 

7 males, mean age 45 yrs; chronic PLP; traumatic upper limb amputations

 

Randomised, DB, cross‐over; 2 wk wash‐out; central pharmacy randomisation

End of treatment at 30 days

 

None

 

3

8

Schwenkreis 2003

 

16

 

14 males; median age 62 yrs; at least 12 mos PLP; upper limb amputation

Randomised, DB, parallel, CGR

 

End of treatment at 21 days 

One in treatment group due to side effects

5

9

Dextromethorphan

 

 

 

 

 

 

 

 Abraham 2003

 10

5 males, mean age 50 yrs; average of  4.8 mos PLP; severe pain at least 1 mo; majority upper, lower limb malignant amputations; others vascular and trauma

Controlled clinical trial; DB cross‐over; no wash‐out;  3‐period, DB, placebo controlled followed by open phase; non‐involved physician prepared order of administration

After 10 days of each treatment period (DB phase)

None 

 3

 7

 Ketamine

 

 

 

 

 

 

 

 Nikolajsen 1996

 11

 8 males; mean age 47 yrs; average of 4 yrs PLP; with postamputation and phantom pain; upper, lower limb amputation; mostly malignant others trauma, infection, reflex sympathetic dystrophy

 Randomised, DB, cross‐over, 3 days wash‐out; non‐involved doctor prepared, sealed, numbered envelope for each patient containing order of drug

At end of infusion: 45 min

None

 3

 8

 Eichenberger 2008

 20

15 males, median age 57 yrs; mean pain intensity 4.32 on 10 cm VAS, average of 12 yrs PLP

 Randomised, DB, cross‐over, time between infusions 48 hours; drawing of lots by person not involved in study

 30,60 min, 48 hrs after infusion

 One from ketamine alone group did not get saline; two from placebo did not get heat, electrical stimulation

 5

 9

  Anticonvulsants

 

 

 

 

 

 

 

 Gabapentin

 

 

 

 

 

 

 

 Bone 2002

 19

15 males; mean age 56 yrs; PLP ≥ 6 mo; average pain intensity ≈ 6 on VAS; majority lower limb amputations; surgical amputations

Randomised, DB, cross‐over; 1 wk wash‐out; CGR

At 6 wks

Two in treatment group, non‐completion and protocol violation; three in placebo, non‐completion; consent withdrawal

 5

 9

Smith 2005

24

18 males; mean age 52 yrs; average pain intensity four NRS; patients with PLP and RLP; upper, lower limb amputations; vascular, traumatic, cancer, infections; at least 6 mo since amputation

Randomised, DB, cross‐over, 5 wk wash‐out; CGR

At 6 wks

Not described

4

7

Antidepressants

Amitriptyline

Robinson 2004

39

17 males; mean age 44 to 45 yrs; with PLP or RLP; upper, lower limb amputation; vascular, traumatic, cancer, infectious; pain at least 3 mos; pain intensity at 2 NRS

Randomised, DB, parallel

Central pharmacy randomisation

At 6 wks

Two due to side effects

5

9

Calcitonins

Jaeger 1992

21

12 males; median age 59 yrs; with severe PLP, 0 to 7 days after surgery; all except one are lower limb amputations; vascular, traumatic, malignant, infectious; pain intensity at least 3 NAS

Controlled clinical trial, cross‐over, 2 hr wash‐out; DB followed by open phase

Short‐term: 24 hr before and after treatment (double blind); long‐term: 6 mos, 1 to 2 yrs (open phase)

None in short‐term; total of eight patients in long‐term (open phase)

3

6

Eichenberger 2008

20

15 males, median age 57 yrs; mean pain intensity 4.32 on 10 cm VAS, average of 12.41 yrs PLP

Randomised, DB, cross‐over, time between infusions 48 hours; drawing of lots by person not involved in study

30, 60 min, 48 hrs after infusion

One from ketamine alone group did not get saline; two from placebo did not get heat, electrical stimulation

5

9

Opioids

Morphine

Huse 2001

12

10 males; mean age 50 yrs; PLP; upper, lower  limb amputations, pain intensity at least 3 VAS; average time since amputation 16 yrs

Randomised, cross‐over; 4‐wk DB phase, 1 to 2 wks wash‐out; long‐term phase (open) for responders; physician with no contact with patients randomised and kept code

Hourly for pain and side effect; weekly during 4 weeks of DB phase; long‐term 6, 12 mos (open)

None during double blind phase

4

8

Wu 2002

31

19 males; mean age 54 yrs; patients with persistent post amputation pains 6 mos; lower, upper limb amputations; time since amputation 81 mos

Randomised, DB, cross‐over, 24 hrs wash‐out; active‐placebo controlled; block randomisation

30 min after end of infusion

One due to absence of pain before start of infusions

5

9

Anaesthetics

Lidocaine

Wu 2002

31

19 males; mean age 54 yrs; patients with persistent post amputation pain > 6 mos; lower, upper limb amputations; time since amputation 81 mos

Randomised, DB, cross‐over, 24 hrs wash‐out; active‐placebo controlled; block randomisation

30 min after end of infusion

One due to absence of pain before start of infusions

5

9

Bupivacaine

Casale 2009

8

6 males; mean age 70 yrs;

PLP at least 6 mos; lower limb amputation; traumatic, vascular; average pain intensity ≈7

 Randomised, DB, cross‐over, 72 hrs wash‐out; CGR

60 min after injection

none

4

10

DB, double‐blind; CGR, computer‐generated randomisation; NAS, numerical analog scale; VAS, visual analog scale; NRS, numerical rating scale; PLP, phantom limb pain; RLP, residual limb pain; yr, year; yrs, years; wk, week; wks, weeks; hr, hour; hrs, hours; min, minutes; mo, month; mos, months; pt, point

Figures and Tables -
Table 1. Summary of Characteristics of Included Studies
Table 2. Summary of Results

Author,

yr

Intervention

Treatment

Duration

FF‐up

Outcomes

Results

Over‐all

direction

of

efficacy

Adverse

events

NMDA

antagonist

 

 

 

 

 

 

 

Memantine

 

 

 

 

 

 

 

Maier 2003

 1) memantine

30 mg/d; oral

2) placebo

 3 weeks

At

end of

3 weeks

Pain intensity

11 pt NRS;

number of

participants

with ≥50% pain

reduction;NNT;

mood;disability;

adverse

events

No sig diff in

change in

pain level, in

number of

participants with

≥50% pain

relief; depres‐

sion scores;

disability indices

in 2 grps; over‐

all number

severe events

higher in

memantine

 ‐

vertigo,

tiredness,

headache,

nausea,

restlessness,

excitation,

cramps

Wieck 2004

 1) memantine

titrated up to

30 mg/d;oral

2) placebo

 4 weeks

each

treatment

arm

At end

of 4

weeks

of each

arm

Pain intensity

0‐100 VAS;

MEG

recording;

adverse

events

No sig diff in

change in pain

intensity,

cortical

reorganization

in both grps

 ‐

Nausea,

fatigue,

dizziness,

agitation,

headaches

Schwenkreis 2003

 1) memantine

titrated up to

30 mg/d; oral

2) placebo

 3 weeks

 At

end of

3 weeks

Pain intensity

11 pt NRS;

ICI; ICF

No sig diff in

pain intensity;

enhanced ICI;

reduced ICF

 ‐

 Not

described

 Dextro‐

methorphan

 

 

 

 

 

 

 

Abraham 2003

 1)

dextromethor‐

phan

120 mg/d;oral

2)

dextromethor‐

phan

180 mg/d;oral

3) placebo

10 days

each

treatment

arm 

At

end of

10

days of

each

arm

Number of

patients with

≥50% pain

relief; feeling

of well‐being;

sedation

score;

adverse

events

Dextromethor‐

phan grps with

≥50% pain

relief; with signi‐

ficantly better

feeling of well‐

being scores;

with

significantly

lower sedation

scores

 +

none

reported

 Ketamine

 

 

 

 

 

 

 

Nikolajsen 1996

 1) ketamine

0.5 mg/kg

once, IV

infusion

2) placebo

45

minute

each

treatment

arm

At end

of IV

infusion

Pain intensity

0‐100 mm

VAS;adverse

events;McGill;

pressure

pain threshold;

wind‐up like

pain; thermal

stimulus

response;

temporal

summation of

heat‐induced

pain;reaction

time

Sig dec in pain

intensity; in

pain‐evoked by

mechanical

stimulation; inc

in pressure

pain threshold;

no alteration in

temperature

sensitivity in

ketamine group

 +

insobriety,

discomfort,

elevation of

mood

Eichenberger 2008

 1) ketamine

0.4 mg/kg

once, IV

infusion

2) calcitonin

200 IU, once,

IV infusion

3) combination

ketamine/

calcitonin, IV

4) placebo

1 hour

each

arm

At 30,

60

mins,

48

hours

after

infusion

Pain intensity;

number of

patients with

≥50% pain

reduction on

10 cm VAS;

basal

sensory

assessment;

adverse

effects

Sig dec pain

intensity in

ketamine alone

and combination

vs. placebo and

calcitonin; sig

inc in number of

responders in

ketamine alone

and

combination vs.

placebo and

calcitonin; sig

inc in electrical

thresholds with

combination

treatment but no

change in

pressure or

heat thresholds

 +

loss of

conscious‐

ness, light

sedation,

light visual

hallucination,

hearing

impairment,

position /

feeling

impairment

  Anticonvulsants

 

 

 

 

 

 

 

 Gabapentin

 

 

 

 

 

 

 

Bone 2002

 1)

gabapentin

titrated up to

2400 mg or

max tolerable

dose; oral

2) placebo

6 weeks

each arm

weekly

and at

end of

6 weeks

Pain intensity

100 mm VAS;

pain

intensity

difference;

depression

score (HADS)

function (BI);

sleep (SIS);

no. of rescue

tabs; adverse

events

Significantly

greater pain

intensity diff with

gabapentin at

end of

treatment; no

sig diff in

depression

score, function,

sleep, no. of

rescue tablets

with the

treatments

 +a

b

somnolence,

dizziness,

headache,

nausea

 Smith 2005

 1)

gabapentin

titrated up to

3600 mg/d;

oral

2) placebo

 6 weeks

At end

of 6 wks

of each

arm

Pain intensity

0‐10 NRS;

depression

score (CES‐D);

function (FIM);

handicap

(CHART);

satisfaction;

global

improvement

rating; pain

inventory;

McGill

No sig group

diff on any

outcomes at

end of

treatment

 ‐c

not

described

 Antidepressants

 

 

 

 

 

 

 

 Amitriptyline

 

 

 

 

 

 

 

 Robinson 2004

 1)

amitriptyline

10 mg/d

titrated to max

of 125 mg/d;

oral

2) benztropine

mesylate 0.5

mg/d; oral

6 weeks

At end

of 6

weeks

Pain intensity

0‐10 NRS

depression

score (CES‐D);

function (FIM);

handicap

(CHART);pain

inventory;

McGill;

satisfaction

No sig group

diff on any

outcomes at

end of

treatment

 ‐

dry mouth

(more

severe),

dizziness

  Calcitonins

 

 

 

 

 

 

 

Jaeger 1992

1) s‐calcitonin

200 IU, IV

infusion

2) saline

20 minute

IV

infusion;

once

24

hours

after

infusion

(DB);

7‐152

days,

weekly

(open

phase)

Pain intensity

0‐10 NAS in

open phase/

long‐term;

number of

patients with

≥50%,75%

pain relief;

adverse

events

Sig dec in

median pain

intensity with s‐

calcitonin at 24

hours after

infusion; at 1 yr,

62% of patients

with 75% pain

reduction

+

headache,

vertigo,

nausea,

vomiting,

phantom

sensation,

drowsiness,

hot/cold

flushes

Eichenberger 2008

1) ketamine

0.4 mg/kg,

once, IV

infusion

2) calcitonin

200 IU, once,

IV infusion

3) combination

ketamine /

calcitonin, IV

4) placebo

1 hour

each arm

At 30,

60

mins,

48

hours

after

infusion

Pain intensity;

number of

patients with

≥50% pain

relief on 10

cm VAS; basal

sensory

assessments;

adverse

effects

No sig dec in

pain intensity

with calcitonin

vs. placebo at

48 hrs; number

of responders

not significantly

different from

placebo

_

drowsiness,

nausea,

facial

flushing,

hot/cold

flushes,

dizziness

Opioids

Morphine

Huse 2001

1) Morphine

sulfate

titrated up to

300 mg/d or

max tolerable

dose; oral

2) placebo

4 weeks

each arm

(DB)

End of

each

treat‐

ment

phase

of 4

weeks

Pain intensity

10 cm VAS;

number of

patients with

50% pain

reduction;

depression

score; pain‐

related self‐

assessment

scale;

WHYMPI;

BSS; psycho‐

physical

thresholds;

2‐point

discrimination;

attentional

performance;

MEG

Sig pain

reduction during

morphine; 42%

with >50% pain

relief; 8% with

25‐50% pain

relief during

morphine; no

sig change in

perception and

pain thresholds;

significantly

lower attentional

performance

during

morphine;

scores on pain

experience

scale, depres‐

sion score,

WHYMPI, BSS

with no sig

relationship with

pain reduction;

2 of 3 with clear

cortical

reorganization

+

constipation

only sig

adverse

effect among

others e.g.

tiredness,

dizziness,

sweating,

micturition

difficulty,

vertigo,

itching,

respiration

Wu 2002

1) morphine

0.2 mg/kg, IV

infusion

2) lidocaine

4 mg/kg, IV

infusion

3) placebo

(diphenhydra‐

mine)

40

minutes

of IV

infusion

30

minutes

after

end of

infusion

Pain relief 0‐

100% numeric

scale; NNT for

30% pain

reduction;

satisfaction,

sedation

scores,

adverse

events

Sig dec in

phantom and

stump pain

intensity during

IV morphine;

NNT=2;

significantly

higher

satisfaction with

morphine;

no sig diff in

sedation

scores

+

sedation

(but no sig

diff with other

groups)

Anaesthetics

Lidocaine

Wu 2002

1) morphine

0.2 mg/kg, IV

infusion

2) lidocaine

4 mg/kg, IV

infusion

3) placebo

(diphenhydra‐

mine)

40

minutes

of IV

infusion

30

minutes

after

end of

infusion

Pain relief 0‐

100% numeric

scale; NNT for

30% pain

reduction;

satisfaction;

sedation

scores;

adverse

events

No sig dec in

PLP vs.

placebo; NNT=

3.8; significantly

higher

satisfaction with

lidocaine vs.

placebo; no sig

diff in sedation

scores

_

sedation

scores not

significantly

different

from

placebo

Bupivacaine

 Casale 2009

 1)

bupivacaine

2.5 mg/ml,1ml,

contralateral

myofascial

injection

2) placebo

(saline)

Injections

given

once

After

one

hour

 Pain intensity

0‐10 VAS;

pain intensity

difference;

phantom

sensation;

mirror

displacement

in healthy

limbs; adverse

effects

 Sig pain relief

with

bupivacaine;

reduction in

phantom

sensation in

6 of 8 patients

 +

 none

yr, year; d, day; mins, minutes; NRS, numerical rating scale; NNT, number needed to treat; VAS, visual analog scale; sig, significant; dec, decrease; inc, increase; grps, groups; grp, group; max, maximum; ICI, intracortical inhibition; ICF, intracortical facilitation; IV, intravenous; DB, double‐blind; MEG, magnetoencephalography; HADS, Hospital Anxiety and Depression Scale; BI, Barthel Index; NRS, numerical rating scale; CES‐D, Center Epidemiologic Depression Scale; FIM, Functional Independence Measure; CHART, Craig Handicap Assessment and Reporting Technique; NAS, numerical analog scale; WHYMPI, West‐Haven Yale Multidimensional Inventory; BSS, Brief Stress Scale; apain intensity; bmood, sleep, function; cpain intensity, mood, function, handicap, satisfaction

Figures and Tables -
Table 2. Summary of Results
Comparison 1. memantine vs. placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 change in pain intensity Show forest plot

2

52

Std. Mean Difference (IV, Fixed, 95% CI)

0.24 [‐0.31, 0.79]

Figures and Tables -
Comparison 1. memantine vs. placebo
Comparison 2. gabapentin vs. placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 change in pain intensity Show forest plot

2

Mean Difference (Fixed, 95% CI)

‐1.16 [‐1.94, ‐0.38]

Figures and Tables -
Comparison 2. gabapentin vs. placebo