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. 2016 Oct 13;2016(10):CD006380. doi: 10.1002/14651858.CD006380.pub3

1. Summary of results.

               
               
Author, year Intervention Treatment
duration 		Follow‐up Outcomes Results Overall direction of efficacy Adverse events
               
BoNTs
BoNT/A
Wu 2012

  1. BoNT/A, 1 mL = 50 units for each injection site

  2. combi l/m, 1 mL = 0.75 mL of 1% lidocaine and 0.25 mL methylprednisolone 40 mg/mL for each painful site

 1 tx episode At 1, 2, 3, 4, 5, 6 mos Change in VAS, change in pressure pain tolerance No significant change in phantom pain and pressure pain tolerance ‐ Not described
NMDA antagonists
Memantine
Maier 2003

  1. memantine 30 mg/d; oral

  2. placebo

 3 weeks At end of
3 weeks		 Pain intensity 11‐point NRS; number of participants with > 50% pain reduction; NNTB;
mood; disability; adverse events		 No sig diff in change in pain level, in number of
participants with > 50% pain relief; depression scores; disability indices
in 2 grps; overall number severe events higher in
memantine grp		 ‐ Vertigo,
tiredness,
headache,
nausea,
restlessness,
excitation,
cramps
Wiech 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‐to‐100 VAS; MEG recording; adverse events No sig diff in change in pain
intensity, cortical
reorganisation 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‐point NRS; ICI; ICF No sig diff in pain intensity;
enhanced ICI; reduced ICF		 ‐ Not
described
Dextromethorphan
Abraham 2003

  1. dextromethorphan 120 mg/d; oral

  2. dextromethorphan 180 mg/d; oral

  3. placebo

 10 days
each
treatment
arm 		 At end of
10 days of
each arm		 Number of participants with ≥ 50% pain relief; feeling of well‐being; sedation score; adverse events Dextromethorphan grps with ≥ 50% pain relief; with sig better feeling of well‐being scores; with sig lower sedation scores + None
reported
Ketamine
Nikolajsen 1996

  1. ketamine 0.5 mg/kg once, IV infusion

  2. placebo

 45 min
each
treatment
arm		 At end of IV infusion Pain intensity 0‐to‐100‐millimetre 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 participants with ≥ 50% pain reduction on 10‐centimetre VAS; basal sensory assessment; adverse events 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‐millimetre 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 weeks of each
arm		 Pain intensity 0‐to‐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‐to‐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 to 152
days,
weekly
(open
phase)		 Pain intensity 0‐to‐10 NAS in open phase/long term; number of participants 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 participants 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
participants with ≥ 50% pain relief on 10‐centimetre 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
treatment
phase of 4
weeks		 Pain intensity 10‐centimetre VAS; number of participants 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% to 50% pain relief during morphine; no sig change in perception and
pain thresholds; significantly
lower attentional performance
during morphine; scores on pain experience scale, depression score, WHYMPI, BSS with no sig relationship with pain reduction; 2 of 3 with clear cortical reorganisation		 + 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 (diphenhydramine)

 40 mins of IV
infusion		 30 mins
after end of infusion		 Pain relief 0‐to‐100% numeric scale; NNTB for
30% pain reduction;
satisfaction; sedation
scores; adverse events		 Sig dec in phantom and stump pain intensity during IV morphine; NNTB 1.9 (95% CI 1.3 to 3.7); significantly higher satisfaction with morphine; no sig diff in sedation scores + Sedation
(but no sig
diff with other groups)
Local anaesthetics
Lidocaine
Wu 2002

  1. morphine 0.2 mg/kg, IV infusion

  2. lidocaine 4 mg/kg, IV infusion

  3. placebo (diphenhydramine)

 40 mins
of IV
infusion		 30 mins
after end of
infusion		 Pain relief 0‐to‐100% numeric scale; NNTB for
30% pain reduction;
satisfaction; sedation
scores; adverse events		 No sig dec in PLP vs placebo; NNTB 3.8 (95% CI 1.9 to 16.6); 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 1
hour		 Pain intensity 0‐to‐10 VAS from 0 no pain to 10 worst pain ever experienced;
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 participants +  None

BI, Barthel Index; BoNT/A, botulinum toxin A; BSS, Brief Stress Scale; CES‐D, Center for Epidemiologic Studies Depression Scale; CHART, Craig Handicap Assessment and Reporting Technique; CI, confidence interval; combo, combination; d, day; DB, double‐blind; dec, decrease; diff, difference; dx, diagnosis; FIM, Functional Independence Measure; grp, group; grps, groups; HADS, Hospital Anxiety and Depression Scale; ICI, intracortical inhibition; ICF, intracortical facilitation; inc, increase; IU, international units; IV, intravenous; l/m, lidocaine/methylprednisolone; max, maximum; MEG, magnetoencephalography; min, minutes; mos, months; NAS, numerical analogue scale; NNTB, number needed to treat for an additional beneficial outcome; NRS, numerical rating scale; PLP, phantom limb pain; sig, significant; SIS, Sleep Interference Scale; tx, treatment; VAS, visual analogue scale; WHYMPI, West Haven‐Yale Multidimensional Pain Inventory; yr, year; apain intensity; bmood, sleep, function; cpain intensity, mood, function, handicap, satisfaction