Repetitive transcranial magnetic stimulation in central post-stroke pain: a meta-analysis and systematic review of randomized controlled trials

 Right now what is your doctor EXACTLY doing to cure your central post-stroke pain? ANYTHING AT ALL? The keyword there is cure!

Repetitive transcranial magnetic stimulation in central post-stroke pain: a meta-analysis and systematic review of randomized controlled trials

Ying Liu^1†Runqing Miao^2†Hui Zou¹Qian Hu³Shao Yin⁴Fengya Zhu^5*

• ¹Department of Acupuncture and Rehabilitation, Traditional Chinese Medicine Hospital of Renshou County, Meishan, China
• ²Department of Preventive Treatment, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
• ³Department of Hematology, Meishan City People's Hospital, Meishan, China
• ⁴School of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
• ⁵Traditional Chinese Medicine Department, Zigong First People's Hospital, Zigong, China

Background: The rehabilitation of central post-stroke pain (CPSP) is a complex clinical challenge, and repetitive transcranial magnetic stimulation (rTMS) has been widely applied in the research of neurofunctional recovery following stroke. However, there is currently no reliable evidence-based medicine supporting the efficacy of rTMS in central post-stroke pain. This review aims to evaluate the effects of rTMS on central post-stroke pain.

Methods: Following the PRISMA guidelines, we conducted searches on PubMed, Cochrane Library, Embase, Web of Science, CNKI, and Wan Fang Data Knowledge Service Platform. We searched for randomized controlled trials (RCTs) investigating the use of rTMS in treating central post-stroke pain, and conducted screening based on inclusion and exclusion criteria. Characteristics of the included RCTs were extracted. The heterogeneity of the trials was assessed using the I2 statistic. Meta-analysis was performed using Stata 17 software. Bias risk and methodological quality were evaluated using the Cochrane RoB 2 tool and the Pedro scale.

Results: A total of six randomized controlled trials involving 288 patients met our inclusion criteria. In our analysis, rTMS was more effective in treating patients with CPSP compared to the placebo group (SMD=-1.15, 95% CI: −1.69, −0.61, P < 0.001). Furthermore, results from subgroup analysis indicated no statistically significant difference in the improvement of pain for durations exceeding 6 months when comparing rTMS to conventional treatment (SMD=-0.80, 95% CI: −1.63, 0.03, P = 0.059).

Conclusion: TMS can alleviate pain in CPSP patients and improve their motor function, but its effects on depression, anxiety, and MEP-latency are not significant.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, CRD42024497530.

1 Introduction

Stroke is one of the diseases with high global incidence, disability rates, and mortality rates (Zhang et al., 2020). Despite comprehensive rehabilitation treatments, most stroke patients experience varying degrees of recovery in motor and sensory functions. However, some patients still suffer from persistent pain on the affected side of the body after a stroke. This pain, occurring after a stroke and associated with the damaged area while excluding other causes, is referred to as CPSP (Radiansyah and Hadi, 2023). Although the onset time of CPSP may be related to the severity and progression of the condition, more than half of the cases manifest within the initial months following a stroke (Klit et al., 2009; Osama et al., 2018; Vukojevic et al., 2018). The incidence rate ranges from 1% to 35% (Dub and Mercier, 2011; Hansen et al., 2012). Many patients may experience various forms of pain concurrently with sensory abnormalities, such as searing, pressing, pulsating, or freezing sensations, numbness, and decreased sensation (Kumar, 2009; Klit et al., 2011). CPSP significantly impacts the sleep, emotions, and overall quality of life for stroke patients, hindering the implementation of effective rehabilitation treatments. The pathogenesis of CPSP is not fully understood, and its treatment remains challenging. Currently, the primary approach involves medications for neuropathic pain. Existing evidence suggests that even with the use of high-dose medications, pain relief is often difficult to achieve for the majority of CPSP patients (Scuteri et al., 2020; Singh et al., 2020; Choi et al., 2021; Mohanan et al., 2023). Additionally, these medications are associated with various side effects (Banerjee et al., 2013; Kim, 2014) and may lead to drug dependence (Kumar and Soni, 2009).

rTMS provides a non-invasive, painless method for studying and treating neuropathic pain states (Lefaucheur, 2016). By applying a magnetic field to the cerebral cortex, it induces electric currents, influencing neural electrical activity. This, in turn, regulates cerebral blood flow and neurotransmitter expression to alleviate pain. Currently, it is recommended by relevant treatment guidelines for various pain conditions (Winstein et al., 2016; Lefaucheur et al., 2020). In addition to its impact on the target area, the synaptic effects produced by rTMS contribute to its distal therapeutic effects (Hallett et al., 2017), but there is no uniform standard for therapeutic parameters in the treatment of CPSP using rTMS. Diverse treatment parameters, including stimulation frequency, target site, and duration of therapy, yield varying analgesic effects. Traditionally, low-frequency (LF) rTMS, defined as stimulation below 1 Hz, has been shown to reduce cortical excitability, whereas high-frequency (HF) rTMS, with frequencies above 1 Hz, exerts the opposite effect (Cruccu et al., 2007; Bai et al., 2022). Previous studies investigating the analgesic effects of rTMS on PSP have discovered that HF-rTMS (5–20 Hz) can effectively alleviate PSP-related pain (Pazzaglia et al., 2018). Compared to single and short-term interventions, multiple sessions and longer durations of intervention have been found to produce superior analgesic outcomes (Hosomi et al., 2013; Ramger et al., 2019).

The meta-analytic review conducted by McDonnell and Stinear (2017) indicated that, in stroke patients, the M1 of the non-affected hemisphere did not exhibit heightened activation during both active muscle contraction and rest, as evidenced by the absence of significant disparities in the parameters of aMT (active motor threshold), rMT (resting motor threshold), and MEPs (motor evoked potentials) when compared to those of healthy controls. This finding suggests that directly enhancing the excitability of the affected M1 may confer greater therapeutic benefits than indirectly suppressing the excitability of the unaffected M1 in facilitating motor recovery following stroke. Numerous previous studies have also discovered that LF-rTMS and continuous theta-burst stimulation (cTBS) not only suppress the amplitude of MEPs in the stimulated M1, but also enhance the MEP amplitude in the non-stimulated M1 (Di Lazzaro et al., 2011; Boddington and Reynolds, 2017). The increased cortical excitability within the unstimulated M1 may be associated with an elevated intrinsic excitability of excitatory interneurons responsible for glutamatergic non-NMDA receptor activity (Heide et al., 2006).

In studies utilizing a rat model of thalamic pain, it has been observed that neuronal structural damage occurs in the lesion area following cerebral hemorrhage or infarction, leading to increased neural excitability. Such alterations may precipitate a range of clinical manifestations, including limb pain and motor functional impairments (An et al., 2019). Other animal experiments have also demonstrated that CPSP reduces the functional connectivity between the VPL and S1/S2 (primary and secondary somatosensory cortices), responsible for perceiving pain location, intensity, and duration, while enhancing connectivity between the thalamus (involved in attention, cognitive abilities) and amygdala (associated with emotional aspects of pain assessment) (Sweet et al., 1971), rTMS can alleviate this abnormal connectivity (Gruart and Delgado-García, 1994).

In recent years, some reviews have summarized the impact of rTMS on pain (Pan et al., 2022; Cheng et al., 2023; Mohanan et al., 2023; Radiansyah and Hadi, 2023), suggesting that rTMS may have a beneficial effect in alleviating pain. However, some reviews primarily focus on exploring the mechanisms and concentrate on conditions such as fibromyalgia, postherpetic neuralgia, malignant neuropathic pain. There is limited analysis in these reviews regarding the clinical evidence of rTMS in treating CPSP. The effectiveness of rTMS for CPSP has not yet received sufficient support from evidence-based medicine. Therefore, to establish the relationship between rTMS and the relief of CPSP, we conducted a systematic review and meta-analysis of published randomized controlled trials. This meta-analysis aims to provide the latest evidence for the use of transcranial magnetic stimulation in the treatment of CPSP.

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