Emerging neural modulation techniques for the management of phantom limb pain: Evidence from randomized controlled trials

Table 1 Summary of randomized controlled trials with nerve stimulation in phantom limb pain

Ref.	Design	Population	Group	Intervention	Stimulation location	Control	Outcome
Gilmore et al[12], 2019; Gilmore et al[13], 2019	Multicenter, double-blinded, RCT	Lower extremity amputees (n = 26)	I: n = 12; C: n = 14	8 weeks of PNS	Femoral and sciatic, with needle electrode 0.5-3 cm from nerve trunk	Sham stimulation for 4 weeks, followed by a crossover of additional 4 weeks PNS	Responders with ≥ 50% reductions in average pain: I: 58%, 7/12 (weeks 1-4) vs C: 14%, 2/14 (weeks 1-4); P < 0.05. I: 67%, 8/12 (weeks 5-8) vs C: 14%, 2/14 (weeks 1-4); P < 0.05. I: 67%, 6/9 (12 months) vs C: 0%, 0/14 (end of the placebo period); P < 0.001
Albright-Trainer et al[14], 2022	Single center, open label, RCT	Lower extremity amputees (n = 16)	I: n = 8; C: n = 8	Standard medical therapy in combination with 8 weeks of PNS	PNS leads implanted approximately 1-3 cm distant from the femoral and sciatic nerves	Standard medical therapy alone	Responders with ≥ 50% reductions in average pain: I: 100%, 5/5 vs C: 50%, 4/8 (8 weeks); I: 100%, 5/5 vs C: 86%, 6/7 (3 months). Opioid consumption: I > 60% decrease vs C > 200% increase (the end of week 8)
Kapural et al[16], 2024; Kapural et al[17], 2024	Multicenter, double-blinded, RCT	Unilateral lower-limb amputees (n = 170)	I: n = 85; C: n = 85	HFNB for day 28-365, with a 30-minute session/day	Cuff electrode wrapped around the damaged nerve, and approximately 1 cm from nerve terminus	Sham stimulation with sub-therapeutic ultra-low frequency for day 28-91, followed by a crossover of HFNB for day 91-365	Day 28-91 responders with ≥ 50% reductions in average pain: I: 24.7%, 21/85 vs C: 7.1%, 6/85; P < 0.01 (30 minutes post treatment); I: 48.1%, 37/77 vs C: 22.2%, 18/81; P < 0.001 (120 minutes post treatment). Opioid usage: I: 6.9 MED/day vs C: 3.6 MED/day reduction, not significant. Day 91-365 average NRS pain: By month 12, combined cohort = 2.3 ± 2.2 points (95%CI: 1.7-2.8; P < 0.0001), 30 minutes post treatment; 2.9 ± 2.4 points (95%CI: 2.2-3.6; P < 0.0001), 120 minutes post treatment. Opioid usage: Combined cohort: 6.7 ± 29.0 MED/day reduction from baseline to month 12 (P < 0.05)
Vats et al[19], 2024	Single center, double-blinded, RCT	Trauma amputees (n = 19)	I: n = 10; C: n = 9	10 sessions of rTMS given over 2 weeks	rTMS at the DLPFC contralateral to the amputation site. Surface electrodes on abductor pollicis brevis, ground on wrist	Sham stimulation	VAS: I: 6.50 (8.00-5.25) at baseline to 0.00 (0.75-0.00, P < 0.0001) at the end of the therapy, 0.00 (1.00-0.00, P < 0.001) at 15 days post treatment, 1.00 (2.00-0.00, P < 0.01) at 30-days post treatment, 0.50 (1.75-0.00, P < 0.01) at 60 days post treatment. C: No significant difference
Kikkert et al[22], 2019	Single center, double-blinded, RCT	Unilateral upper-limb amputees (n = 15)	I: n = 15; C: n = 15	4 consecutive tDCS sessions spaced at least 1 week apart	Anodal over S1/M1 missing hand cortex, cathodal over contralateral supraorbital area, sham electrodes on intact hand S1/M1 and supraorbital area	Sham stimulation	Percentage change of PLP ratings: I: -6.1, immediately after tDCS; I: -20.3, end of experimental session. C: +42.9, immediately after tDCS; C: +28.3, end of experimental session
Gunduz et al[23], 2021	Multicenter, double-blinded, 2 × 2 factorial, RCT	Unilateral traumatic lower limb amputees (n = 112)	Active tDCS/active MT: n = 29, sham tDCS/active MT: n = 28, active tDCS/covered MT: n = 28, sham tDCS/covered MT: n = 27	20 minutes tDCS stimulation a daily session for 10 days	The anodal electrode was placed over the M1 contralateral to the amputation side and the cathodal over the contralateral supraorbital area	Sham stimulation	VAS: No interaction between tDCS and MT groups (F = 1.90, NS). In the adjusted models, there was a main effect of active tDCS compared to sham tDCS (beta coefficient = -0.99, P < 0.05) on phantom pain. The overall effect size was 1.19 (95%CI: 0.90-1.47)

RCT: Randomized controlled trial; I: Intervention; C: Control; PNS: Peripheral nerve stimulation; MED: Morphine equivalent dose; NRS: Numerical rating scale; rTMS: Repetitive transcranial magnetic stimulation; DLPFC: Dorsolateral prefrontal cortex; VAS: Visual analog scale; tDCS: Transcranial direct current stimulation; S1: Primary somatosensory cortex; M1: Primary motor cortex; PLP: Phantom limb pain; MT: Mirror therapy; NS: Not significant.