Repetitive Transcranial Magnetic Stimulation for phantom limb pain in land mine victims: A double-blinded, randomized, sham-controlled trial

This study puts light on how high-frequency rTMS on the contralateral primary motor cortex of traumatic amputees induced a clinically significant pain reduction up to 15 days after treatment without any major secondary effect.

Land mines, one of the world’s most disabling public health hazards, results in approximately 15,000 to 25,000 victims each year. After trauma-related limb amputation for land mine injury, one of the significant causes of disability is the presence of phantom limb pain (PLP). PLP is a neuropathic syndrome characterized by pain felt in the patients’ remaining perception of the amputated limb after partial or complete deafferentation. This pain is usually described as a stabbing, throbbing, burning, or cramping sensation. PLP is present in up to 87% of all amputees and is considered a challenging condition because of its negative effect on quality of life and lack of treatment response, particularly in patients with traumatic-related amputations.

The high prevalence of PLP after amputation and its lack of treatment response have resulted in major efforts to develop interventions to decrease the pain in affected patients. In light of PLP mechanisms, repetitive transcranial magnetic stimulation (rTMS) has been tested in this condition as a tool to block the maladaptive plasticity in the sensorimotor cortex. rTMS applied daily over the primary motor cortex (M1) has shown pain relief effects in other neuropathic pain syndromes such as post stroke pain and spinal cord injury pain. Some previous reports have also suggested analgesic effects of rTMS in subjects with PLP. There have been only 3 trials testing rTMS in PLP. Two were small pilot studies and other was a randomized clinical trial with 27 subjects. A recent meta-analysis judged this trial as a high risk of bias study due to deficient randomization method, which led to an unbalanced distribution between the intervention groups. There was a need for larger, rigorously designed studies, particularly of longer courses of stimulation. This study hypothesized that 10 Hz rTMS for 2 weeks over M1 contralateral to the PLP could significantly decrease the level of pain compared with sham stimulation.

Rationale behind research:

• Some previous trials have tested the analgesic effects of rTMS in subjects with PLP but they were deficient in some way or the other
• This had created a need for larger, rigorously designed studies, particularly of longer courses of stimulation. In order to cater this unmet need, present study was conducted

Objective:

To assess the immediate and sustained effects of a larger dose of real rTMS of M1—10 sessions—on PLP compared with sham rTMS in land mine victims.

Study outcomes

Primary Outcomes:

Primary end point of the study was the score change in visual analogue scale (VAS) for pain. This self-evaluation scale ranges from 0 to 10 as visually described in centimeter units, 0 cm indicates no pain and 10 cm the worst pain possible. Response was defined as a reduction of ≥30% compared with baseline at 15 and 30 days after treatment.

Secondary Outcomes:

• Zung Self-Rating Depression Scale: This is a 20-item self-report scale measuring 4 common characteristics of depression: pervasive affect, physiological equivalents, other disturbances, psychomotor activities. Minimum score is 20 and maximum score is 80. Four categories from ‘‘normal’’ to ‘‘severely depressed’’ are based on specific score ranges. 
• Zung Self-Rating Anxiety Scale: This is a 20-item questionnaire on the basis of scoring in 4 groups of manifestations: cognitive, autonomic, motor, and central nervous system symptoms. The total scores range from 20 to 80, meaning normal range to extreme anxiety levels.

Time Points: Baseline and at 15 and 30 days after treatment

Outcomes:

• Baseline: There were no significant differences in demographic and clinical characteristics at baseline between the groups.
• Primary Outcome: A significantly greater mean percentage reduction in pain intensity (VAS score) was found 15 days after treatment in the active group than sham stimulation group (53.38 6 53.12% vs 22.93 6 57.16%; mean between-group difference = 30.44%, 95% confidence interval [CI], .30–60.58; P = .03). However, no significant differences between groups were found 30 days after treatment (37.74 6 52.39% vs 14.97 6 53.88%; mean between-group difference = 22.76%; 95% CI, 6.25 to 51.79; P = .12). Nineteen subjects (70.3%) attained a significant clinical response (pain reduction > 30%) in the active group than with 11 (40.7%) in the sham group 15 days after treatment. However, no statistically significant between-group difference was found 30 days after treatment. A higher proportion of subjects obtaining a substantial clinical benefit (pain reduction >50%) was also found in the active treatment group compared with the sham stimulation group 15 days after treatment (17 [62.9%] vs 9 [33.3%]; RR = 1.88; 95% CI, 1.02–3.46). This difference also showed a statistical trend toward significance when evaluated 30 days after treatment (13 [48.1%] vs 6 [22.2%]; RR = 2.16; 95% CI, .96–4.85).

Figure 1: Average scores of pain at baseline and after 15 and 30 days of treatment

• Secondary Outcome: Effects of rTMS on pain level were assessed using a repeated measure analysis of variance. There was a significant main effect of group of treatment and time (F1,104 = 7.54, P < .01; F2,104 = 19.49, P < .0001). The analysis showed a significant interaction term (group per time; F2,104 = 3.25, P = .04). Post hoc tests revealed a significant decrease in VAS scores, 15 and 30 days after finishing the intervention in active group. No statistical significance between-group difference was found when comparing the absolute VAS scores at day 15 (mean between group difference = 1.42; 95% CI, .07 to 2.93; P = .06) or day 30 (mean between-group difference = .86; 95% CI, .59 to 2.31; P = .24) after treatment. In relation to the scores of depression and anxiety scales, a main effect of time was found (F2,104 = 4.55, P = .01; F2,104 = 7.91, P < .0001), without significant group of treatment effects (F1,104 = .11, P = .7; F1,104 = .07, P = .7) or interactions terms (F2,104 = 1.32, P = .27; F2,104 = .2, P = .81). No statistically significant between-group difference was found on comparing the absolute scores of depression and anxiety scales at day 15 or day 30 after treatment. 

Figure 2: Average scores of depression at baseline and after 15 and 30 days of treatment

Figure 3: Average scores of anxiety at baseline and after 15 and 30 days of treatment

The present study showed that treatment with 10 Hz rTMS of contralateral M1 during 2 weeks in traumatic amputees with PLP induced a clinically significant pain reduction up to 15 days after treatment than with sham stimulation. No serious adverse effects were found indicating that rTMS was a safe and effective in patients with PLP caused by land mine explosions.

Previous studies had shown some beneficial effects of rTMS on PLP. These reports have evaluated either the effects of low frequency rTMS (1 Hz), which may induce an opposite effect. In an initial case report, Topper et al evaluated the effect of rTMS series on phantom pain like syndrome in 2 patients with long-lasting brachial plexus avulsion. They underwent 10 and 1 Hz rTMS during 15 days, separated by 4 and 6 weeks, respectively (at 110% of RMT, 12-minute duration) over the contralateral posterior parietal cortex to the injured limb. The authors reported a maximum pain reduction of approximately 60% and 23.6%, during the rTMS treatment compared with baseline; however, the pain decrease was not maintained in the long-term. Similarly, Di Rollo and Pallanti in 1 patient with PLP of traumatic origin, applied 15 sessions of low-frequency rTMS (thirty 20-second trains at 80% of RMT, 15 minutes) over the ipsilesional motor cortex, showing a pain reduction of 33.3% at the end of the third week of treatment and a slight decrease (16.6%) at the follow-up visit (3 weeks after the last session).

Also, a significant reduction in depressive and anxiety symptoms after 30 days after the intervention without any differences between treatment groups, indicating an effect not attributable to rTMS.