rTMS in the Treatment of Neuropathic Pain

Fig. 10.1

Practical algorithm on the implementation of rTMS in the treatment of neuropathic pain

Despite their statistical significance, rTMS effects are rather modest and short lasting on a clinical level, and this is a major limit for a routine therapeutic use in patients with chronic pain. Invasive epidural stimulation can still be considered as the best approach for long-term management, unless the clinical relevance of maintenance treatment based on repeated sessions of rTMS is demonstrated. Increasing the total number of pulses per session and repeating the sessions for several days or weeks are surely able to enhance and prolong rTMS-induced analgesia. Table 10.1 presents the current evidence of the analgesic effects produced by sham-controlled protocols of repeated sessions of high-frequency rTMS of the motor cortex. Future investigation should also address the interindividual variability of the analgesic effects provided by cortical stimulation, the priming influence of various analgesic medications, and the characterization of the significant predictors of efficacy.

Table 10.1

Evidence of the analgesic effects produced by sham-controlled protocols of repeated sessions of high-frequency rTMS of the motor cortex using a figure-of-eight coil

Reference	Study type and population	Intervention (parameters of stimulation)	Outcome measures, main results, conclusion (grade)
Khedr et al. (2005)	Parallel arms: active vs. tilted coil 48 patients (active, 28; control, 20): trigeminal neuralgia (24), post-stroke pain (24)	20 Hz, 80 % RMT, hand M1 contralateral to pain side, 2000 pulses, 5 sessions	Significant analgesic effect of active rTMS on both VAS and LANSS up to 2 weeks post-rTMS Active rTMS: 45 % (end of rTMS) to 40 % (+2 weeks) of responders. Sham rTMS: 5 % (end of rTMS) to 2 % (+2 weeks) of responders High grade for rTMS efficacy (large sample size; no adverse effects)
Ahmed et al. (2011)	Parallel arms: active vs. tilted coil 27 patients (active, 17; control, 10): amputees with phantom limb pain	20 Hz, 80 % RMT, hand M1 contralateral to pain side, 2000 pulses, 5 sessions	Significant analgesic effect of active rTMS on both VAS and LANSS up to 2 months post-rTMS Increase in serum beta-endorphin after active, but not sham, rTMS, without any correlation with VAS, LANSS, or HDRS/HAM-A changes High grade for rTMS effects (duration of follow-up; no adverse effects)
Fricova et al. (2013)	Parallel arms: active vs. sham coil 36 patients (active vs. control, unknown numbers): 23 orofacial pain and 13 not defined patients	10 Hz, 85–95 % RMT, M1 contralateral to pain side, 600 pulses, 5 sessions	Significant analgesic effect of active rTMS on VAS compared to sham after the 1st to the 3rd session (−1.5 vs. −0.5 point) No change in tactile detection threshold after active and sham rTMS Low grade for rTMS effects (small sample size, few pulses per session, and poorly described population, methods, and results; no adverse effects)
Fricova et al. (2013)	Parallel arms: active vs. sham coil 23 patients (active, 13; control, 10): facial pain secondary to dental surgery (11), secondary to trigeminal nerve lesion (6), without clear organic substrate (6)	20 Hz, 95 % RMT, M1 contralateral to pain side, 720 pulses, 5 sessions	Significant analgesic effect of active rTMS on VAS compared to sham after the 3rd session to 2 weeks after the last session (−2 vs. −0 point) Similar reduction of warm detection threshold after active and sham rTMS. Reduction of tactile detection threshold after active rTMS Low grade for rTMS effects (small sample size, few pulses per session, and poorly described population, methods, and results; no adverse effects)
Hosomi et al. (2013)	Crossover (random order), active vs. realistic sham; washout period, 17 days at least 64 patients: post-stroke pain (52), spinal cord lesion (7), phantom limb pain (3), root or nerve lesion (2)	5 Hz, 90 % RMT, M1 corresponding to the painful region, 500 pulses, 10 sessions	Significant analgesic effect of active rTMS on VAS compared to sham, but only 4 % of difference in VAS reduction rate between the two groups Significant improvement of SF-MPQ and PGIC after active rTMS. PGIC change not lasting. No change in BDI Medium grade for rTMS effects (large sample size, duration of treatment, but few pulses per session; minor and transient adverse effects (12 % active group vs. 6 % sham group): headache, dizziness)
Khedr et al. (2015)	Parallel arms: active vs. tilted coil 34 patients (active, 17; control, 17): relative to cancer or its treatment	20 Hz, 80 % RMT, hand M1 contralateral to pain side, 2000 pulses, 10 sessions	Significant analgesic effect of active rTMS on VRS, VAS, and LANSS scores at the end and up to 2 weeks after rTMS protocol. No more effect at 4 weeks after rTMS protocol Antidepressant effect lasting up to 6 weeks after active rTMS (HDRS) Medium grade for rTMS effects (poor clinical definition of the patients; no adverse effects)

RMT rest motor threshold, M1 primary motor cortex, VAS visual analog scale, LANSS Leeds assessment of neuropathic symptoms and signs pain scale, HDRS Hamilton depression rating scale, HAM-A Hamilton anxiety rating scale, SF-MPQ short-form McGill pain questionnaire, PGIC patient global impression of change, BDI Beck depression inventory, VRS verbal rating scale

Nowadays, various noninvasive and invasive methods of neurostimulation are developing increasingly as therapeutic options for chronic neuropathic pain. Therefore, the main challenge for pain specialists may be to define the best neurostimulation protocol to treat a given patient, according to the pathophysiological mechanisms of pain involved in this patient.

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