. 2017 Aug 7;10:1861–1870. doi: 10.2147/JPR.S124664

Table 4.

Details of papers assessed to be of moderate quality with reasons for potential bias identified

Reference	Methods	Participants	Outcomes	Risk of bias
Bone et al²⁵	Gabapentin RCT, double-blind, cross-over, inactive placebo Population PLP >4/10 for 6 months	33 referred 19 recruited (16 males) 14 completed 15 lower limb amputees	PLP VAS difference from baseline (p=0.025 at 6 weeks point, otherwise ns) HAD (ns) Bartel index (function), ns Sleep interference (ns)	Small sample size Inactive placebo Multiple tests performed VAS 6 weeks result may be artifact
Maier et al³¹	Memantine Double-blind, placebo-controlled RCT PLP for at least 1 year (>4/10) 4 weeks follow-up	36 participants Mixed upper/lower limb Mixed major/minor amputation	PLP VAS (ns)	Mixed group Short follow-up Small sample size Unclear how PLP and SP are differentiated
Nikolajsen et al²⁹	Memantine Double-blind, cross-over RCT PLP or neuropathic pain postamputation >3/10	19 participants (14 males) 4 nerve injury 7 finger amputations 1 upper limb amputation 7 lower limb amputations	Daily mean VAS (ns) MPQ (ns) Evoked pain (ns)	Mixed group of conditions/amputations Small sample size Worst pain used, so unclear effect on PLP
Nikolajsen et al²⁸	Ketamine Double-blind, cross-over RCT, inactive placebo	11 participants (8 males) PLP or SP 3 finger amputations 2 upper limb 6 lower limb 7 cancer 1 trauma 3 surgical	VAS (p<0.05) MPQ (p<0.05) Evoked pain (p<0.05 for some areas only)	Mixed PLP and SP Mixed amputation/level Small sample size Short duration of effect Side effects of ketamine
Robinson et al²⁴	Amitriptyline RCT, active placebo (benztropine) Amputation-related pain for at least 6 months	39 participants Mixed upper/lower limb 7 PLP, 6 SP, 24 both, 2 other pain	Average VAS (ns) MPQ (ns) BPI (ns) Function (FIM), ns Satisfaction with life (ns) Handicap (CHART), ns	Mixed amputation Mixed PLP and SP Small sample size
Smith et al²⁶	Gabapentin Double-blind, cross-over RCT, inactive placebo	24 participants Lower limb amputation PLP or SP (VAS >3 in the last month)	Composite NRS (0–10), ns Global benefit score (p<0.05) BPI (ns) MPQ (ns) Depression (CES-D), ns Function (FIM), ns Satisfaction with life (ns) Handicap (CHART)	Mixed pain PLP/SP Small sample size Inactive placebo
Wiech et al³⁰	Memantine Double-blind, cross-over RCT, inactive placebo	8 participants Upper limb 4 above elbow 3 shoulder 1 hand PLP only	Mean VAS during treatment (ns) MEG scan (cortical reorganization), ns	Small sample size Inactive placebo Mixed upper limb sample
Wu et al³²	Lidocaine and morphine Double-blind, cross-over RCT, active placebo (diphenhydramine)	31 participants PLP or SP or both Upper/lower limb amputees (9/22)	Pain VAS (lidocaine SP − p<0.01) (morphine SP − p<0.01 and PLP − p<0.001) Sedation VAS pain relief score (%) NNT (lidocaine – SP 2.5 for 30% reduction) (morphine – SP 2.1 for 30% reduction and 1.9 for 30% reduction in PLP)	Mixed sample of amputees PLP and SP Small sample size for multiple calculations Short follow-up (80 minutes)
Wu et al³³	Mexiletine and morphine Double-blind, cross-over RCT, inactive placebo	60 enrolled, 45 two drug periods, 35 all three phases	Pain VAS change from baseline Morphine pain relief vs placebo p=0.0003 and vs mexiletine p=0.0003 Morphine NNT for 33% pain reduction =4.5 Side effects high in morphine group	Mixed sample of amputees PLP and SP Large dropout Inactive placebo

Abbreviations: BPI, brief pain inventory; CES-D, Center for Epidemiologic Studies Depression Scale; CHART, Craig Handicap Assessment and Reporting Technique; FIM, Functional Independence Measure; HAD, hospital anxiety and depression scale; MEG, Magnetoencephalography; MPQ, McGill pain questionnaire; NNT, number needed to treat; NRS, numerical rating scale; ns, no statistical difference; PLA, phantom limb awareness; PLP, phantom limb pain; PLS, phantom limb sensation; RCT, randomized controlled trial; SP, stump pain; VAS, visual analog scale.