新型經皮脈衝射頻電刺激器於腕隧道症候群之應用：從實驗室到臨床

Abstract

腕隧道症候群是因正中神經在手腕部位被壓迫所引起的一種常見周圍神經病變。傳統治療方法像是配戴護腕,類固醇注射,用藥,復健或手術，但療效和副作用都有所限制。脈衝射頻刺激已經成為一種嶄新療法,用於治療各種慢性神經病理性疼痛。本論文的目的，是要從動物實驗到人體臨床試驗,開發並評估一種創新經皮脈衝射頻治療裝置,用以治療腕隧道症候群。 在動物實驗部分,首先利用矽膠管壓迫正中神經，建立大白鼠腕隧道症候群模型。治療前後量測其前足的機械性疼痛閾值。接著給予±5伏特、±10伏特與±22.5伏特的經皮脈衝射頻刺激。結果顯示,單次經皮射頻刺激使手術組大白鼠的疼痛耐受度回復到手術前的80%。利用纖維蕊絲刺激測試檢視射頻治療12週後的疼痛反應,高強度射頻刺激相較於低強度，呈現更持久的止痛效果。 基於此研究，及避免太高強度經皮電刺激產生的副作用，我們開發設計出一種低強度、可攜式經皮脈衝射頻治療裝置，將其命名為腕部刺激器 Carpal Stim。它能產生500千赫頻率、25毫秒脈衝寬度、2赫茲脈衝頻率的雙相正弦波。這小型裝置使用CR2430鋰電池供電，並由低功率MSP430微控制器控制。此一嶄新裝置將運用於後續的臨床試驗當中。 第一代腕部刺激器進行了初次人體臨床試驗，共14位腕隧道症候群病患參與。它輸出500千赫頻率、25毫秒脈衝寬度、2赫茲脈衝頻率、10伏特峰值電壓之刺激訊號。治療15分鐘後，病患的疼痛視覺評量表評分從6.7降至3.1。透過重複刺激能維持兩週的止痛效果。整個治療過程安全,無併發症或副作用發生。 最後，進行一項隨機、雙盲、對照組控制的臨床試驗，共58位腕隧道症候群病患參與，比較腕部刺激器與對照組的療效。刺激參數設定為500千赫頻率、25毫秒脈衝寬度、2赫茲脈衝頻率、±6.6伏特峰值電壓。主要療效指標雖無顯著差異，但相較對照組，腕部刺激器在兩週時的疼痛與麻痺感評分有顯著改善及統計上意義。整體而言,此療法安全有效。 綜合以上，本論文從動物實驗到人體臨床試驗，開發並評估了一種經皮脈衝射頻治療裝置，用於腕隧道症候群。腕部刺激器是一種前景看好的非侵入性、非藥物療法，在兩週內可有效紓解病患疼痛。後續研究可持續優化參數，以提升療效。

Carpal tunnel syndrome (CTS) is a common peripheral neuropathy caused by compression of the median nerve at the wrist. Conventional treatments include splinting, medication, steroid injection, physical therapy and surgery. These, however, have limitations in terms of efficacy and side effects. Pulsed radiofrequency (PRF) stimulation has emerged as a novel therapy for chronic neuropathic pain conditions. The purpose of this dissertation was to develop and evaluate an innovative transcutaneous PRF device for CTS from preclinical studies to clinical trials. In the animal studies, a rat model of CTS was established by compressing the median nerve with a silicone tube. Mechanical pain sensitivity of the paw was quantified before and after PRF. Transcutaneous pulsed radiofrequency stimulations at voltage amplitudes of ±5V, ±10V, and ±22.5V were applied. Results showed that single transcutaneous PRF application increased pain tolerance to 80% of baseline compared with sham surgery rats. Pain behaviors were assessed up to 12 weeks after PRF treatment using von Frey filaments. High voltage PRF produced sustained antinociception compared to low voltage PRF. Next, a low voltage and portable transcutaneous PRF device named Carpal Stim was designed and developed. Carpal Stim delivered biphasic sinusoidal waves at 500kHz frequency and 25ms pulse width, along with pulse frequency (2Hz). The small device was powered by a CR2430 lithium coin cell battery and controlled by a low power MSP430 microcontroller. This novel device was used for the following clinical trials. A first-in-human preliminary clinical trial was conducted in 14 CTS patients using first generation Carpal Stim. It generated a 500 kHz signal delivered in 25 ms pulses width at 2 Hz frequency and 10volt amplitude. The mean visual analog scale (VAS) for pain reduced from 6.7 to 3.1 after 15 minutes of PRF treatment in Day 1. Repeated PRF stimulation could maintain pain relief for 2 weeks. No complications or side effects occurred. Finally, a randomized, double-blind, sham-controlled trial was performed in 58 CTS subjects using current Carpal Stim device versus sham device. It generated a 500 kHz signal delivered in 25 ms pulses width at 2 Hz frequency and ± 6.6volt amplitude Although the primary endpoint of responder rate was not significantly different, Carpal Stim resulted in statistically significantly greater pain reduction on the numeric rating scale and GSS numbness score at 2 weeks. Carpal Stim was also safe and well-tolerated. In conclusion, this dissertation presents the development and evaluation of a novel transcutaneous PRF device for CTS from preclinical studies to clinical trials. Carpal Stim is a promising non-invasive, non-pharmacological treatment option that can produce pain relief in CTS patients in 2 weeks. Further studies on parameters and treatment protocol optimization are warranted to improve efficacy.