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

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