A Randomized Controlled Trial of 5 Daily Sessions and Continuous Trial of 4 Weekly Sessions of Repetitive Transcranial Magnetic Stimulation for Neuropathic Pain

Koichi Hosomi; Kenji Sugiyama; Yusaku Nakamura; Toshio Shimokawa; Satoru Oshino; Yuko Goto; Tomoo Mano; Takeshi Shimizu; Takufumi Yanagisawa; Youichi Saitoh


Pain. 2020;161(2):351-360. 

In This Article

Abstract and Introduction


We conducted a multicenter, randomized, patient- and assessor-blinded, sham-controlled trial to investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) in patients with neuropathic pain (NP). Patients were randomly assigned to receive 5 daily sessions of active or sham rTMS of M1 corresponding to the part of the body experiencing the worst pain (500 pulses per session at 5 Hz). Responders were invited to enroll in an open-label continuous trial involving 4 weekly sessions of active rTMS. The primary outcome was a mean decrease in a visual analogue scale of pain intensity (scaled 0–100 mm) measured daily during the daily sessions in an intention-to-treat population. Secondary outcomes were other pain scores, quality-of-life measures, and depression score. One hundred forty-four patients were assigned to the active or sham stimulation groups. The primary outcome, mean visual analogue scale decreases, was not significantly different (P = 0.58) between the active stimulation group (mean, 8.0) and the sham group (9.2) during the daily sessions. The secondary outcomes were not significantly different between 2 groups. The patients enrolled in the continuous weekly rTMS achieved more pain relief in the active stimulation group compared with the sham (P < 0.01). No serious adverse events were observed. Five daily sessions of rTMS with stimulus conditions used in this trial were ineffective in short-term pain relief in the whole study population with various NP. Long-term administration to the responders should be investigated for the clinical use of rTMS on NP in the future trials.


Neuropathic pain (NP) is defined as "Pain caused by a lesion or disease of the somatosensory nervous system." by the International Association for the Study of Pain.[27] Neuropathic pain can arise from a variety of causes: stroke, spinal cord injury, phantom limb, herpes zoster infection, radiculopathy, diabetic neuropathy, and so on. Characteristic symptoms include spontaneous continuous pain, shooting pain, allodynia, and hyperalgesia with sensory deficits. It is regarded as a distinct clinical entity despite a large variety of causes because of common clinical features and putative pathophysiological mechanisms, which include both peripheral and central sensitization.[4] Tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin are recommended as first-line treatment in NP.[11] Number needed to treat for 50% pain relief, however, ranges from 3.6 to 7.7 on these drugs,[11] and no strong recommendation has been made in interventional treatment of NP.[6,7] Thus, available treatments are not yet adequate in many patients, and NP still disturbs patients' daily activities and reduces quality of life (QOL).[5] There is a critical need for novel therapeutic methods to treat intractable NP. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) is a noninvasive brain-stimulation method that has garnered interest as an alternative treatment for intractable NP.[21] Repetitive transcranial magnetic stimulation can potentially induce therapeutic brain plasticity on the stimulated area and various neural structures related to pain perception.[15,18,20] We previously conducted a pilot randomized, patient- and assessor-blinded, sham-controlled, crossover trial to assess the efficacy and safety of 10 daily rTMS treatments (500 pulses per session at 5 Hz) for patients with intractable NP in 7 centers in Japan. The trial results show that daily rTMS of M1 provides transient modest pain relief.[16] Recent meta-analyses and therapeutic guidelines report that high-frequency (≥5 Hz) rTMS of M1 is safe and has a transient pain-relieving effect.[6,21,25,26,30] Repetitive transcranial magnetic stimulation devices have not been approved in clinical use for treating NP in most of the countries including Japan; nevertheless, many clinical trials reported positive results. It reflects that no well-designed large clinical trials of rTMS for NP have been strictly conducted. There is uncertainty around the previous promising findings derived from the poor quality of evidence. Because clinical use of rTMS requires a regulatory approval in Japan, we planned a large strict clinical trial to obtain a regulatory approval, which was designed based on the results of our previous pilot study.[16] This trial investigated the efficacy and safety of 5 daily sessions of rTMS of M1 compared with sham stimulation in patients with intractable NP.